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Year One: First Things First > Protein Structures and Functions > Flashcards

Protein Structures and Functions Flashcards

1
Q

What do proteins provide?

A

· Carrier functions-trafficking oxygen, importing and exporting molecules such as glucose or ions
· Metabolic functions- Enzyme cascades producing and utilizing energy glycolysis or TCA cycle
· Form parts of the Cellular machinery-sometimes as parts of ribonucleoprotein complexes such as spliceosomes, ribosomes
· Make up structural scaffold- microtubules, nucleosomes
· Sensing molecules-cell surface receptors and their ligands

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2
Q

Why is the orientation of amino acid side chains important?

A

The side chains form the specific contacts within and between proteins, cofactors and enzyme substrates or ligands.

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3
Q

How is the basic structure of an amino acid determined?

A

By the valency of carbon

amino acid has a tetrahedral arrangement of atoms around a central alpha carbon

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4
Q

Describe the basic structure of an amino acid

A

Linked to the C-alpha carbon are a carboxyl and amino group, a single hydrogen and a variable side chain usually represented by R and a hydrogen group

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5
Q

Explain the ionic properties of amino acids

A

· The carboxylic acid and amine groups of the amino acids are readily ionized.
· This means that the NH2 group can act as a base and acquire a hydrogen becoming an NH3+ ·

Similarly the carboxyl group readily donates a hydrogen acting as an acid becoming COO-

· The various groups of an amino acid are in equilibrium with the surrounding environment

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6
Q

Explain the states of amino acids in low, neutral and high pH

A

· at high pH the carboxyl group donates a hydrogen and becomes negatively charged
at low pH the amine group acquires a hydrogen becoming positively charged

· And At neutral pH the molecule has an overall balanced charge and contains both positively and negatively charged groups and is described as a zwitterion

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7
Q

Which amino acid does not have two isomers?

A

Glycine because the R group is a hydrogen.

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8
Q

How does D and L isomers arise?

A

there are two possible isomers for every amino acidbecause ofthepossibility of forming two different enantiomers (stereoisomers) aroundthecentral carbon atom.

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9
Q

What nature is the C-alpha?

A

chiral, assymetrical

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10
Q

Describe the difference between L and D amino acids

A

· L-amino acids are found in naturally occurring proteins of all living organisms.

D amino acids do exist in nature and can be found in the cell walls of some bacteria but are also sometimes used as therapeutics

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11
Q

How do peptide bonds form?

A

condensation reaction releasing H2O

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12
Q

What is a residue?

A

· Each repeating unit of the polypeptide chain is termed a residue

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13
Q

How does polarity arise in amino acids?

A

Amino (N) and Carboxyl (C) terminus

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14
Q

How is the R chain oriented and what is the implication?

A

· arranged in a trans conformation such that the variable side chain is alternately orientated.

This orientation occupies space with the lowest energetic requirement

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15
Q

What is the difference between cis and trans orientation of amino acids energy wise?

A

· 0.1% peptide bonds have a less energetically favorable cis arrangement- where the side chain is located on the same side

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16
Q

How do secondary structures arise?

A

· They are formed from intra-chain hydrogen bonding ie bonding between different parts of the same chain

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17
Q

How do beta pleated sheets arise and how are they connected?

A

· Held together by intramolecular hydrogen bonds · the chain is folded to form a parallel or anti-parallel arrangement
· The orientation of the strands determines the relative positioning of the groups forming the hydrogen bonds affecting their strength and stability

· the beta strands are connected either by longer omega loops or short turns of the polypeptide chain.

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18
Q

Explain the difference between antiparallel and parallel arrangement of beta strands

A

Anti-parallel arrangement of beta strands produces a beta sheet with greater stability and strength because hydrogen bonds in anti-parallel beta sheet are linear

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19
Q

How do beta bends/reverse turns form?

A

· involve four amino acid residues with a hydrogen bond between the C=O group of the first residue and the N–H group of the fourth.

Type I and type II β bends differ in respect of the torsion angles for the residues.

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20
Q

How do beta loops form?

A

· Non-regular motif, consisting of a loop of six or more amino acid residues and any amino acid sequence.

  1. Residues that make up the beginning and end of the loop are close together

· Turns and loops lie on the surfaces of proteins and thus often participate in interactions between proteins and other molecules.
· Recognition role of proteins, such as the recognition of specific antigens by antibodies.

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21
Q

Explain how alpha helices form(3)

A

· Hydrogen bonds are 4 residues apart
· Alpha helices form a right-handed helix with 3.6 residues per turn and approximately 0.54 nm per turn · The side chains form the specific contacts within and between proteins , cofactors and enzyme substrates or ligands.

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22
Q

How does the tertiary strcuture arise?

A

· Combining secondary structures such as alpha helices, beta sheets and beta turns

these bonds and forces are acting between the same chain in tertiary structure

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23
Q

Give an example of a protein in its tertiary structure in a membrane

A

· the seven transmembrane domain of the thyroid stimulating hormone receptor or the CXCR4 chemokine receptor
· The alpha helices in each case span the membrane and anchor the structure in the membranes

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24
Q

How are quaternary structures formed?

A

· combining two or more folded polypeptide chains, the same bonds and forces influence quaternary structure
· however a key difference is that these bonds and forces are acting between different polypeptide chains

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25
Q

Give an example of protein at a quartenary structure

A

· hemoglobin Quaternary structure is formed by combining four chains 2 Hbα and 2 Hbβ polypeptides

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26
Q

Explain the various sizes and shapes of proteins with different examples

A

· The size and complexity of functional proteins vary hugely Haemoglobin comprises of 4 chains , but insulin has just 2,

Glutamate synthase may have between 8 and 12 depending on the organism,

· ribosomes are ribonucleoproteins comprising of both RNA and large numbers of multi-chain proteins.

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27
Q

What does the formation of structure and the ability for a protein to function depend on?

A

Often dependent on cofactors

· Cofactors may also be needed for the structural integrity and correct folding of the protein. For example, in hemoglobin both haem and iron are present, in insulin zinc is critical for its structure and function.

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28
Q

What are cofactors?

A

Acofactoris a non-protein chemical compound that is required for the protein’s biological activity

They are active centres for NAD and FAD

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29
Q

Are cofactors limited to tertiary structures?

A

No, they can be found with quaternary structures

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30
Q

Describe the orientation of water solube proteins

A

· Hydrophilic residues are mostly on the external surface.
· Hydrophobic residues are usually buried inside the protein
· Not all water soluble proteins are globular and some form filaments eg actin, tubulin or cortexillin but in all these the hydrophilic amino acids face outside

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31
Q

Describe the orientation of proteins in non-aqueous environments and give an example

A

· hydrophilic residues may be buried internally. · the Hydrophobic residues of membrane bound receptors may anchor a protein in the hydrophobic environment of the membrane eg the CXCR4 chemokine receptor

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32
Q

How is folding of the polypeptide chain determined?

A
  • the amino acid sequences
  • the molecular structure and properties of its amino acids
  • the molecular environment (ligands, cofactors, solvents & salts)
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33
Q

Give examples of charged amino acids

A

aspartic acid, glutamic acid, lysine and arginine

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34
Q

Describe charged amino acids

A
  1. negatively and positively charged and
  2. charged groups within the amino acids are either carboxylic acids or amines

• charged amino acids are also polar in nature but are sufficiently different from the polar amino acids

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35
Q

Give examples of non-polar or hydrophobic amino acids

A

alanine, valine, leucine, isoleucineSpecial case: methionine

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36
Q

Describe sulfur contaning amino acids and give examples

A

sulphur containing amino acid is cysteine so whilst having a group containing both make some sense,

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37
Q

Give examples of polar amino acids

A

Serine, threonine
• Histidine is also sometimes considered as a charged amino acid

Tyrosine histidine and tryptophan are in a sub group the polar aromatic amino acids

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38
Q

What is the difference between polar amino acids and the charged amino acids?

A

Polar amino acids contain nitrogen and oxygen atoms as part of carbonyl or secondary amide groups rather than carboxyl or amine groups

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39
Q

Why are glycines found in turns or loops?

A

It is small and provides more freedom of movement in the chain.

40
Q

How does peptide bonds affect protein folding?

A

· The peptide bond imparts restrictions on the folding of the chain
• flat planar structure that has a fixed arrangement because of delocalised electrons associated with the carbonyl group and amide groups. t
the peptide bond behaves as if it were a double bond but is not.

  • However, the rest of the chain has rotational freedom around the bonds of the c alpha atom ie the c alpha- c prime and c alpha and the nitrogen. The peptide bond itself is rigid.
  • And this provides the freedom of movement to dynamically form the complexity of secondary, tertiary and quaternary structure eg alpha helicies.
41
Q

What can happen to amino acids with large side chains?

A

• Amino acids with large side chains may be restricted in their rotation

42
Q

What is the intrinsic state of proteins?

A

· All molecules have an intrinsic energetic state and this energetic state determines its conformation and minimization of this drives changes toward a minimum energetic state

43
Q

What determines arrangement of atoms?

A

• The minimisation of this energetic state (the free energy of a molecule “G”) determines the most favourable arrangement of the atoms (conformation)

44
Q

What is ∆G?

A

• the change in free energy upon folding is called ∆G

45
Q

Is ∆G negative or positive upon simultaneous fold?

A

It is negative

46
Q

What is the free energy of structure affected by?

A

· by the environment and the other molecules that it interacts with
• for example aqueous vs lipid environment,
• ligands, cofactors or ions etc
• and changes in that environment as a result of binding a ligand or cofactor can result in conformational changes and a different structure and thus protein structure is dynamic

47
Q

What is the difference between covalent and non-covalent bonds?

A

with Non- covalent bonds being weakernbeing only 1/20th the strength of covalent bonds

• However the number of non-covalent bonds that contribute to the overall structure of a protein is much greater, and are numerous by comparison

48
Q

Recall the different types of non-covalent bonds

A

Charge or electrostatic attractions
van der waals attractions
hydrophobic interactions

49
Q

Describe charge or electrostatic attractions of non-covalent bonds

A

· falls off exponentially as distance increases, affected by electrostatic environment (aqueous environment)
· Hydrogen bonds (transient bonds similar in some respects to covalent bonds)

50
Q

Describe van der waals attraction

A

Dipole- weak forces occur between two atoms

· determined by their fluctuating charge
· attraction at a close distance is balanced by repulsion due to proximity that is determined by the Van der Waals radius of an atom,

51
Q

Describe hydrophobic interactions and how they minimise disruption of water network

A
  • (water is a polar molecule) hydrophobic interactions minimise disruption of water network – ie the fourth weak force
  • water is a polar molecule that forms a network of polar interactions, disruption of this network comes at an energetic cost
  • a protein will adopt a structure that minimises that network
  • for example forming a globular structure with hydrophilic groups on its external surface in an aqueous environment
52
Q

How are disulphide bonds formed?

A
  • These bonds are formed from an oxidative reaction between cysteines that come into proximity because of folding
  • and can form between cysteines on the same polypeptide chain (tertiary structure) or between different polypeptide chains (quaternary structure)
53
Q

What is the role of covalent bonds in a folded structure?

A

Covalent bonds involved in the formation and stabilization of a folded structure

54
Q

Recall diseases related to protein misfolding

A
  • Huntingtin Htt (Huntington’s)
  • Amyloid-beta Ab (Alzheimer’s) beta-amlyloid plagues form
  • prion protein (PrPSc) Creutzfeldt–Jakob disease and variant CJD
  • alpha-synuclein (Parkinson’s disease)
  • Serum amyloid A (AA amyloidosis)
  • islet amyloid polypeptide IAPP (Type 2 Diabetes)
55
Q

Which misfolding form aggregates?

A

Secondly mis-folded proteins

56
Q

How does cystic fibrosis arise from protein misfolding?

A

mis-folded proteins result in cellular processing that lead to their degradation.Lack of protein contributes to disease.

57
Q

How does Cystic fibrosis arise?

A

· the most common mutation is a deletion of Phenylalanine at residue 508 of the cystic fibrosis transmembrane conductance regulator (CFTR)- a single codon deletion
· CFTR regulates chloride ions crossing the cellular membrane
· DF508del leads to mis-folding of the protein whilst it is still in the ER
· This is recognised by the cellular machinery that identifies and processes misfolded protein
· This results in ubiquitination, trafficking to the proteasome and degradation
· An example of somatic deletion

58
Q

Why does mis-folding occur? (6)

A
  • somatic mutations in the gene sequence leading to the production of a protein unable to adopt the native folding
  • errors in transcription or translation leading to the production of modified proteins unable to properly fold
  • failure of the folding machinery
  • mistakes of the post-translational modifications or in trafficking of proteins
  • structural modification produced by environmental changes
  • induction protein mis-folding by seeding and cross-seeding by other proteins
59
Q

How does Alzheimers arise? (8)

A
  1. b-Amyloid (Ab) is a small protein released because of proteolysis from a larger transmembrane protein known as Amyloid Precursor Protein APP
  2. beta amyloid is normally lying within the membrane
  3. When it accumulates in isolation of the rest of the protein it misfolds and then forms beta sheets which in turn form stacked multimers.
  4. Flat planar monomeric sheets form, those in turn aggregate to form stacked sheets of oligomers
  5. The oligomers extend to form protofibrils that further aggregate forming an amyloid fibrils
  6. Protofibrils interdigitate with those of another sheet forming amyloid fibril
  7. The aggregation of b-amyloid in the brains of Alzheimer’s patients is a feature of the pathology of the disease .
  8. These interfere with the workings of the synapse, particularly in the hippocampus. Gradually, higher order insoluble, aggregates form, deposited in plaques, damaging the neuronal cells of brain.
60
Q

What kind of modification occurs in Alzheimer’s?

A

an example of a post-translational modification of the protein resulting in proteolysis leading to disease pathology

61
Q

How does induced protein misfolding occur?

A

Mis-folded proteins(prion proteins) that interact with other normal proteins
· Through this interaction they induce mis-folding of the normal protein and polymerisation
· by seeding and cross-seeding by mis-folded
· Oligomers form fibrils of mis-folded protein- induction is a change in energy that represents a lower energetic state in the oligomeric structure than in the correctly folded molecule in isolation

62
Q

Why are aggregate structure more stable?

A

· This process is reliant upon the concept of energy minimisation ∆G
• It is a dynamic process brought about by the interaction of molecules resulting in a more stable aggregated structure

63
Q

What is a protein sequence domain?

A

a pattern of amino acids that are found in related genes or proteins

64
Q

What are motifs and domains?

A
  • Simple secondary structures (folds) combine to form structural motifs or larger functional domains
  • Such units of protein structure are commonly found and are conserved across functionally related proteins but may not be related in sequence nor direct evolutionary pathway
65
Q

What is a motif?

A
  • a minimum arrangement of independently forming secondary structures combining recognisable folds (arrangements) across many different proteins
  • A combination of two or more secondary structures to form a recognisable localised folded arrangement of structure
  • Motifs are organised or combined into larger structural and functional domains
66
Q

How are motifs coded for?

A

• They are coded by segments of genes; they are modular in nature and relate back to a heritable unit of genetic structure for example functional domains often but not always relate to a single exon within a gene

67
Q

What is a domain?

A

a conserved part of the protein sequence that can function independently to the rest of the protein chain. They are a region that has a specific function

• a more complex structure at the tertiary or quaternary level, often involving interaction between distant parts of a protein or motifs

68
Q

What is a functional domain?

A

• typically larger and may or may not be a contiguous segments of a single polypeptide chain
• A functional would comprise of multiple modular domains each with a different function

69
Q

Give an example of a functional domain

A

• SRC (pronounced SARK) kinase would have multiple domains, both kinase and regulatory domains each with different functions, the SH4 domain is unique to but the others are modular units combined elsewhere in different proteins

70
Q

How many structural motifs exist?

A

1400-1500 different structural motifs (folds)

71
Q

What motifs are found in the TATA box binding proteins?(3)

A

a beta-alpha-beta.

the polypeptide chain of a single beta strand associated with the beta sheet then connects directly to the alpha helix of the motif,

the polypeptide chain then forms a series of four antiparallel beta strands making up the remainder of the beta sheet on the right, followed by the longer alpha helix sitting on top of the beta sheet.

72
Q

What do beta-alpha-beta motifs do to DNA through TATA box binding proteins?

A

The overall structure comprises of two such motifs together they bind to and distort the DNA recruiting other proteins to form the initiation complex allowing transcription to start

73
Q

What are the two common motifs?

A

the EF hand and the Greek Key

74
Q

What is the EF hand?

A

EF hand is a calcium binding motif found in for example in Calmodulin & Troponin-C , it combines with a metal ion calcium shown.

There are 2 EF hands at either end of an alpha helix going.

75
Q

What is the Calmodulin in EF hand?

A

Calmodulin is part of the mechanism for sensing intracellular calcium levels and calcium binding to the

EF hand results in a conformational change in the protein

76
Q

What is the Greek Key motif?

A

consists of a specific arrangement of beta strands within an antiparallel beta sheet, but is one motif that is so common it isn’t generally associated with a specific function.

77
Q

What is the beta barrel motif?

A

arrangement of beta strands wrapped around to form a circular tunnel that looks somewhat like a wicker basket,a similar to alpha/beta barrel which is also surrounded by alpha helices

These motifs are also associated with a diverse set of functions

78
Q

What is the beta-alpha-beta motif?

A

Parallel strands of a beta sheet are interlinked with a alpha helix

79
Q

Where in the DNA are DNA binding motifs inserted?

A

inserted into the major groove of DNA in a sequence specific manner

80
Q

Recall the four DNA binding motifs studied

A

· Helix loop helix – eg Max & Mad also Ca2+ binding
· Helix turn helix –eg Cro, tryptophan, & lac repressors
· Leucine Zipper – eg GCN4
· Zinc Finger – eg hormone receptors

81
Q

What is the role of functional domains?

A

anchoring the protein in the membrane

82
Q

What is the most common form of fucntional domains?

A

Bundles of alpha helicesless commonly lone helices or a bundle of beta sheets

83
Q

Describe an example of a functional domain in the membrane

A

The 7-transmembrane domain arrangement of alpha helices is commonfound in rhodopsin, TSHr, many pharmacological receptors and receptors for some polypeptide hormones

84
Q

Describe an example of domain shuffling

A

Mammalian phospholipase C, this contains 4 different recognisable domains. Each of these is found individually
found in other proteins troponin C , bacterial phospholipase C etc
Since each of these are linked to a segment of the gene

85
Q

How is haemoglobin and myoglobin examples of functional domains?

A

Each chain of haemoglobin has a tertiary structure very similar to that of the single myoglobin chain, strongly suggesting evolution from a common ancestral O2- binding polypeptide

86
Q

Why are alpha helices referred to as recognition helix?

A

An alpha helix can fit within the major groove of DNA – this structure forms the specific contacts with the DNA bases

87
Q

What is common between the binding of the motifs to DNA?

A

only in the dimeric form and the Helix loop Helix typical of this

88
Q

Describe the helix-loop-helix(6)

A
  1. One of the largest families of dimerizing transcription factors.
  2. bHLH proteins bind to a consensus sequence called the E box
  3. Exists as hetero (different monomers) and homodimers (identical monomers)
  4. The central portion of the HTH is made from overlapping helices that form a structure enabling dimerisation, this dimerization domain forms a structure that resembles a twisted rope.
  5. The terminal part of the lower opposing helices contain basic amino acids that interact with the major groove of the DNA – giving rise to the b/HLH functional domain.
  6. The central part hold the recognition helices in place
89
Q

Give examples of Helix-loop-Helix

A

MYOD, MYF5, MAX, TCF4- master gene regulators

90
Q

Describe the Leucine Zipper motif(4)

A
  1. Formed from 2 contiguous alpha helices and like the HLH, is a dimeric protein formed from two polypeptide chains.
  2. The dimers again “zip” together in the top “stalk” to form a short “coiled-coil”
  3. The coil is held together by hydrophobic interactions down opposing sides of the helix
  4. As in the b/HLH basic amino acids dominate the lower part of the helix and since they are basic repel each other opening the terminal ends like the jaws of a clamp and interact with the DNA major groove of the negatively charged DNA
91
Q

Why is heteromonomers and homodimers a key characteristic in helix-loop-helix motifs?

A

• allow different dimers to regulate different genes as a consequence of each monomer that comprises the dimer recognising a different sequence in the DNA

92
Q

Give examples of Leucine Zipper motif

A

“cFon, cJun

93
Q

How are motifs involved in DNA transciption?

A

These combine to form domains that have specific functions such as DNA binding, dimerization, and other regulatory functions

These motifs are conserved across all phyla

94
Q

Describe helix-turn-helix and their interaction with DNA

A

two short helices orientated at right angles to each other & connected by a “turn” but this is not a beta turn

  1. The motif is found in both prokaryotic and eukaryotic DNA binding proteins for example the CRO and lambda repressors, & homeobox proteins CRO and Lambda are homodimers,
  2. CRO therefore recognises a palindromic sequence and by binding DNA represses transcription
  3. Only the recognition helix interacts with the nucleotide sequence itself
  4. the helix turn helix locates the recognition helix within the major groove
95
Q

Describe zinc finger motifs

A

An alpha helix and a beta sheet held together by non-covalent interactions with zinc

  1. The alpha helix of each motif interacts with the major groove of DNA and recognises a specific DNA sequence.
  2. different parts of the dimer contribute to the DNA binding domain in addition to each of the motifs,

4.allowing regulation of transcription

96
Q

Recall examples of zinc finger homone receptors

A

Glucocorticoid, Mineralcorticoid oestrogen, progesterone, as well as Vit D receptors

Year One: First Things First (27 decks)

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