Functions and Dysfunctions of Protein Processing (3) Flashcards
Genetic Code
- nucleotide sequence of gene into aa sequnece of protein using mRNA
- start: AUG
- stop: UAG, UGA, UAA
Sickle Cell Anemia
- arises from missense mutation of 6th codon in allele of gene for human B-globin (HBB), subunit of adult hemoglobin
- mutation changes GAG–> GTG (substitutes Val which is hydrophobic for Glu which is negatively charged and hydrophilic)
- alters conformation of HbA –> causes it to aggregate and form rigid, rod-like structures
- deforms RBC into sickle-like shape; deformed = poor oxygen capacity and tend to clog capillaries, further restricting blood supply to tissues
Duchenne Muscular Dystrophy (DMD)
- large in-frame and out-of frame deletions to the dystrophin gene leads to partially or nonfunctioning dystrophin protein
- OOF deletion result in little/no expression of dystrophin protein, giving rise to severe form of DMD
- 1:3500 males
- leads to muscle wasting (wheel chair confinement)
Activation of Amino Acids
Two steps:
-Aminoacyl tRNA synthetase catalyzes addition of AMP to COOH end of AA
-AA is transferred to cognate tRNA
NET RESULT: amino acid is selected by its codon
RIbosomal Subunits
PROKARYOTES: 70S: 50S large and 30S small
EUKARYOTES: 80S: 60S large and 40S small
Polysome
clusters of ribosomes simultaneously translating a single mRNA molecule
- each synthesizing a polypeptide
- makes protein synthesis more efficient
Streptomycin
binds to the 30S subunit to disrupt the initiation of translation; interferes with 30S subunit association with 50S su
Shiga Toxin
binds to the 60S subunit to disrupt elongation
Clindamycin and erythromycin
bind to large 50S subunit (prok), blocking translation of ribosome
-erythromycin (commonly used to treat pertussis)
Tetracyclines
bind to 30S subunit, blocking entry of aminoacyl-tRNA to ribosomal complex (disrupt elongation)
Chloramphenicol
inhibits peptide transferase (prokaryote/mitoch.)
Puromycin
causes premature chain termination
- resembles the 3’ end of the aminoacylated- tRNA
- enters A site and adds to the growing chain
- forms a puromycylated chain, leads to premature chain release
- exact mechanism is unknown
- more resistant to hydrolysis
- stops the ribosome
Cytoplasmic Pathway
for proteins destined for cytosol, mitochondria, nucleus, and peroxisomes
-protein synthesis begins and ends one see ribosomes in cytoplasm
no signal= stays in cytoplasm
N terminal hydrophobic alpha helix= mitochondrion
Lys Arg rich= nucleus
C-terminal SKL= peroxisome
Secretory Pathway
for proteins destined for ER, lysosomes, plasma membranes, or for secretion
- translation begins on free ribosomes but terminates on ribosomes sent to ER
- first 20 aa residues of polypeptide has ER targeting signal sequences
NH3 coiled= ER signal
Lys Asp Glu Leu (c-terminal KDEL)= ribosomes/ER lumen
Trp-Rich domain= secretory vesicle
Mannose 6-phosphate= lysosome
N-terminal apolar region (stop transfer sequence)= membrane
I-cell disease
severe form of lysosomal storage disease
- tagging of lysosomal proteins with mannose 6P is defective (high plasma levels of lysosomal enzymes)
- developmental delays and physical manifestations
- hepatomegaly; developmental delays; death by 7
Chaperones
protect protein and help fold into property tertiary structure
-example: HSP70
chaperonins
barrel shaped compartments that admit unfolded proteins and catalyze their folding in an ATP-dependent manner
-Example:HSP60
proteolytic cleaveage
converts inactive forms to active enzymes by unmasking alive site (e.g. trypsinogen and chymotripsinogen to trypsin and chymotrypsin)
converts nascent precursor proteins to mature ones (ex. proinsulin to insulin)
Glycosylation
O-glycosylation= -OH bound -residue affected= Ser, Thr
N-glycosylation= acid-amide (-CONH2)
-residue affected= Asn, Gln
Phosphorylation
phosphate linked via esterification (-OH functional group)
-residue affected= Ser, Tyr, The; also Asp and His
Disulfide Bond formation
oxidation to achieve covalent linkage of cysteine residues (-SH groups)
-residue affected= Cys
Acetylation
covalent linkage to amine (-NH3+)
-residue affected= Lysine
Post-translational modifications of collagen
most abundant structural protein in vertebrates which undergoes a lot of modifications after synthesis
- modifications important for assembly of collagen
- Ehlers-Danlos syndrome= overly flexible joints, walls of blodo vessels, intesetines or uterus may rupture
- epidermolysis Bulls Simplex= blisters on skin
- Nevo Syndrome and Bruck Syndrome
Alzheimers Disease
- loss of memory, cognitive function, language
- APP–> AB(aggregation)–> plaques in brain
- hyperphosphorylation of Tau (neurofibrillary tangles)- intracellular
- mutations in APP and Tau cause familial forms of AD
- Brain aging is the common denominator for Sporadic form
Parkinsons Disease
- impairment of fine motor control
- problem with gait and shuffling
- aggregation of alpha-synuclein (AS) protein forms insoluble fibrils which deposit as lewy bodies in dopaminergic neurons in substantial nigra
- results in selective death of these neurons
- symptoms due to reduced availability of dopamine
- mutations in AS cause familial forms of PD
- brain aging is the common denominator for sporadic form
Huntington Disease
- loss of movement and cognitive functions and psychiatric problems
- mutation in Huntington gene–> CAG triplet repeats
- results in polyglutamine repeats in abnormal HTT protein. forms intramolecular H-bonds, which eventually misfold and aggregate
- selective death of cells in basal ganglia cause the symptoms
- 10-26 normal; 36-121=HD gene
Creutzfeldt-Jakob/Kuru/Mad Cow disease
- failing memory, behavioral changes, lack of coordination and visual disturbances
- late stages involve mental deterioration blindness, weakness of extremities, and coma
- memory, visual disturbances
- caused by misfiling of prion proteins
- transmissible- infection by misfiled proteins converts normal proteins to misfiled form
- belongs to transmissible spongiform encephalopathies (TSEs)
- Spongiform- appearance of infected brains, filled with holes and resemble sponges under a microscope
