section 2 Flashcards
Whay else target proteins can do
Give the feedback to the receptor
Can be activation or inhibition of this protein, this will lead to a feedback of reaction and will go to the beginning of the cascade ( often to receptor protein ) inhibitiin ghtem or internalizing them
What can happen to the signal during transmission
Exponential amplification during transmission
Based on the signal receptor, pathways can be divided into 2 main classes
Pathways with cell-surface receptors
Pathways with intracellular receptors
Basic strucutre of a cell surface receptor
Extracellular domain with NH2 end, whic have disulfide bond and glycosylation
Hydrophobic transmembrane domain
Cytoplasmic domain with Co2H
What AAs make transmembrane domain and how many of them are needed for that
20-25 AAs are needed to cross membrane once
Hydrophobic AAs (ala, Ile,Leu,Met,Phe,Val,Pro,Gly)
Ectodomain (NH2) is often rich in ___ for S-S bonds for folding
Cysteine
What secondary structure transmembrane has
Alpha-helix
What does it mean that 3 domains of the receptor are interchangeable
you can put an extracellular part of the receptor on the other receptor of the same strucutre and it will work fine
If the receptor have only an ectodomain what it can do
It can serve as a buffer system, binding to the hormone in the circulation and increasing its half life
What can be the result of cleaved ectodomain in the circulation
The ectodomain cleaved frim the TSH receptor may induce antibodies which binds to the receptor and mimic TSH action ->hyperthyroidism in Grave’s disease
What will happen to cytoplasmic domain of the receptor upon binding of hormone to the ectodomain
conformational change or indicing the intrinsic enzymatic acitvity or recruitng someone
Many signaling proteins are activated by phosphorylation at the AAs:
Serine, threonine and tyrosine on OH group
Who is the phosphate donor in phosphorylation
ATP
Phosphorylation causes
Conformational change of the protein
What signaling proteins that are activated by phosphorylation will perform signal amplification
Kinases
Phosphorylation can be reversed by
Phosphatases
What AAs are phosphorylated usually
Serine and threonine
When tyrosine is usually phosphorylated and what is their role
In the beginning of the cascade
They serve as a docking sites for down signalling rather than further phosphorylation
What is the name for tyrosine domains that will be phosphorylated
SH2 and SH3 domains
3 major types of cell surface receptors
What happens to GPCR upon binding of the signal
G alpha is released and then it goes to adenylyl cyclase or other enzyme to activate it
5 types of Galpha subunits
What type of receptors is the most numerous class
G-protein couples receptors
How many trans membrane alpha-helices has GPCR
7
Examples of endocrine and non-endocrine signals acting through GPCR
Many receptors of non-endocrine signals also act via
G-proteins. Examples: glutamate (neurotransmitter),
thrombin, odorants and photoreceptors
-Examples of endocrine hormone receptors are TRH,
GnRH, TSH, LH, FSH, ACTH, GHRH and oxytocin
Does one hormone is specific to one G-protein?
No, it can use more and also G protein use may change during development and also concentration of hormone
2 types of tyrosine kinase coupled receptors
Receptors with an intergrated (intrinsic) kinase activity
Receptors that recruit a kinase
insulin receptor is in what class of receptors
Intrinsic tyrosine kinase activity
How many parts insulin receptor has
Hetero-tetrameric (2 alpha and 2 beta held together by S-S bonds)
What domain alpha or beta has a transmembrane
β subunit about 618 a.a.: Ectodomain
193 a.a., transmembrane domain 23
a.a., cytoplasmic domain 402 a.a.
Where the most of insulin receptors are
In adipocytes and hepatocytes
Insulin receptor has a homology with what receptor
IGF-1
Sequence of events after insulin binding
Autophosphorylation of
intracellular domain of receptor
Docking and phosphorylation of
IRS-1 and IRS-2 (insulin
receptor substrate)
Activation of two major
signal pathways
Describe Insulin receptor signaling through MAPK pathway
Initiation: receptor and ligand interaction, insulin binds to insulin receptor
The portion that is blue ( cytoplasmic domain - inside the cytoplasm) gets phosphorylated
This phosphorylation leads to another phosphorylation of insulin receprtor (IRS-1)
IRS-1 acts as a docking protein( adaptor ) for GRB-2 , a cascade of adaptor proteins
They come together and form a complex of proteins
MEK gets phosphorylated on 2 serines
MEK phosphorylates ERK on Thr and Tyr
Phosphorylated ERK moves into the nucleus, where ( as a kinase) activate transcription factors SRF and Elk 1-> transcription-> protein
Insulin receptor signaling through PIP3
Ligand binding to the receptror, and it phosphorylayes IRS-1
IRS-2 acts as a docing protein
IRS-2 phosphorylates allows PI3K to connect
PI3K converts PIP2 to PIP3 ( not a cleavage mechanism like in GPCR)
PIP3 allows for doking PKB, which is activated by phosphorylation
Protein kinse B( PKB) phosphorylate GSK3 , inactivating it , now GS kinase cannot add phosphate to inactivate GS, so synthesize of glycogen occurs ( REMOVAL OF INACTIVATOR)
PKB helps in opening GLUT4 and helps in bringing glucose inside the cell
Characteristics of receptors that recruit tyrosine kinase activity
4 alpha helices and homology of the ectodomain (hormon binding site)
Best known receptors of recruited tyrosine kinase activity
Growth hormone, prolactin, leptin
GH signaling pathway
GH binds to the receptor 1. it forces to bring the second part of the complex, which together can recruit JAK-2
Recruitment of JAK2:
phosphorylates itself, the
receptor and other proteins
3 branches of phosphorylated JAK activity
Branch 1: Activation of the
transcription regulatory proteins,
STAT (4 isoforms) ( usually stuck near membrane, but as soon as it is phosphorylated can go inside the nucleus)
v Branch 2: Activation of the MAPK
pathway (as insulin, but JAK2
plays the role of IRS1)
v Branch 3: Activation of PI3K
pathway
Describe JAK-STAT pathway
Binding of the hormone cross-liks adjacent receptors and jaks cross-phosphorylate each other on tyrosines and then phosphorylate the receptor on tyrosines
What does it mean non-classical peptide hormones and examples
IGF is a peptide hormone, though water soluble, it is carried in the circulation bound to a carrier protein
Adipokines: leptin is also example of this group
Neurotransmitters examples that are amino acid derivative
Neither a peptide or hormone, but derived from AAs
Melatonin, serotonin, histamine
Examples of lipid hormones with memebrane receptors
Eicosanoids never classified as steroids, because they are using cell membrane receptors (GPCRs)
And steroids are using nuclear receptors
What 4th category is considered non-classical hormones and through what receptors they function
Lactate, ketone bodies, succinate, FAs ,etc.
GPCRs
To what receptors steroid and thyroid hormones bind
To a family of intracellular receptors which are structurally related adn founf in the cytoplasm or nucleus
Nuclear receptor family
Nuclear receptors function as ____ and how fast they give the response
Nuclear receptors and function as transcription factors
Response is slow since transcription and translation takes time,as well as post-translational modifications
Name ligands for nuclear receptors from classical hormones class, vitamins, metabolic intermediates and products
Classical hormones: thyroid, estrogen, testosterone, progesterone, aldosterone, cortisol
Vitamins: vitamins D and A (cis and trans forms)
Metabolic intermediates: FAs,oxysterols,bile acids,heme,phospholipids, xenobiotics
Mechanism regulating ligans levels
Precursor availability
Synthesis
Secretion
Activatione (prohormone->active hormone)
Deactivation (active hormone->inactive hormone)
Elimination ( hepatic, renal clearance)
Describe the pathway of nuclear receptor signalling mechanism
3 domains that all nuclear receptors will have
DNA binding doamin(a/b)
Nuclear localization signal( the sequence so the protein comes from the cytoplasm into the nucleus) (C/d)
Ligans binding domain (LBD) (E)
sequences of nuclear DNA binding domains
Steroid hormones funciton as homodimers and inward direction sequence
The middle part of the sequence is the most important
RXR heterodimers in direction following each other
Explain chromatin immuniprecipitation (ChIP) sequencing
Factors modulating receptor activity in different tissues
