L1, Insulin Action 1 Flashcards
What blood glucose concentration would signify diabetes?
20-30mM
Type I Diabetes Mellitus: Proportion of cases and cause
- 5% of cases
- Caused by autoimmune destruction of pancreatic b-cells that produce insulin
Type II Diabetes Mellitus: Causative links + Symptoms
Background
- 95% of cases
- Results from acquired insulin resistance; heterologous group of metabolic disorders
- Rapid increase in incidence is linked to a high calorie diet and sedentary lifestyle
- Growing evidence of a genetic basis for susceptibility
Symptoms
- Eye disease
- Cardiovascular disease
- Oral health problems
- Pregnancy complication
- Kidney damage
- Nerve damage
- Diabetic foot
Diabetes Mellitus: Prevalence, No. deaths
Diabetes affects 537 million adults. It caused 6.7 million deaths in 2021
Insulin Metabolism: Production, Key Roles
- Produced in islets of langerhans in pancreas
- Induces glucose uptake (via translocation of glucose transporters from cytosol to PM)
- Signals for production of glycogen from glucose (by activating glycogen synthase)
- These processes occur in both the liver and in muscle tissue
- Stimulates fatty acid production in the liver and inhibits fat breakdown in adipose tissue
- Suppresses gluconeogenesis
Glucagon: Overview
- Produced in pancreas
- Induces production of glucose from glycogen in liver -> glucose release
Binding Domains: Why are they useful? Definition?
- Facilitate protein-protein interactions -> allows complex pathways to be constructed
- Conserved part of protein sequence; independently stable and folded 3D structure; may evolve, function and exist independently
Give 4 key examples of protein binding domains with examples of residues which they bind
- SH2 - pY
- SH3 - PxxP
- PTB - pY
- PH - PIPs
How are protein domains important for recognition and specificity?
- All proteins in a family bind to the same structure
- Each individual domain recognises only a subset of these features
SH2 domain: How does it interact? Relevance of flanking sequence?
- Contains a critical FLVR sequence
- Positive residues interact with negative phosphate
- Sequence variability effects preferred sequence flanking pY -> ensures specificity of response
Outline the structure of the SH2 domain:
- Antiparallel beta-sheet flanked by two alpha-helices
- Arginine of FLVR coordinates the pY phosphate oxygens
SH3 domain: how does it bind? What is the affinity like and how is this relevant?
- Binds to proline-rich sequences with PXXP core motifs
- Two classes
- Weak affinity -> usually require multiple domains
Outline the structure of the SH3 domain:
- Five antiparallel beta-strands in two perpendicular beta sheets
- Hydrophobic ligand binding site of conserved aromatics and variable flanking residues
PTB domain binding + relevance of N-terminal sequence
- Positive residues interact with negative phosphate (recognises pY in NPXpY motif)
- N-terminal sequences are required for high affinity binding and conferring specificity
Give the structure of the PTB domain
- Two orthogonal beta-sheets with a C-terminal amphipathic alpha-helix capping one end of the beta-sandwich
- Peptide N-terminal residues form an additional anti-parallel beta-strand to the second beta sheet
PH domain: What does it bind? How is it useful? How does PH relate to PTB domain?
- Binds phosphate of phosphoinositides (e.g. PIP2)
- Mediates protein-protein and lipid-protein interactions (important in cytosol to membrane translocations)
- PH and PTB are structurally similar but there is not sequence homology
Describe the structure of the PH domain
- beta-barrel of two anti-parallel beta-sheets and amphipathic alpha-helix
- phosphate of PIP3 bind positive side chains in PH domain
SH2 specificity in Src vs Grb:
- Src SH2 binds pYEEI with key serine residue
- Grb SH2 binds pYxN with key tryptophan residue
+ Insulin receptor binding: effect and impact on binding ability
- Tyrosine phosphorylation occurs at YxxM motifs
- The phosphorylated tyrosines become binding sites for SH2 motifs downstream -> facilitated by IRS which acts as a docking molecule
+ How can insulin signalling be attenuated?
- Largely mediated by rapid receptor endocytosis (clathrin coated pits and caveolae) and degradation upon insulin-receptor binding
- Also terminated by tyrosine phosphatases acting on pTyr of the beta subunit of the receptor
+ Molecular basis of diabetes
- Studies have proposed diabetes to be the result of genetically heterogeneous group of disorders
- Molecular and cellular defects in insulin synthesis, secretion and degradation, insulin receptor synthesis ad I-C assembly etc
+ What is the role of PDZ domains? Give two examples from the course where they are found:
- Post synaptic density signalling
- e.g. Syndecan signalling substrates
- e.g. Notch ligands
