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Insulin Signaling: A Molecular View Shuchismita Dutta, Ph.D. Developed as part of the RCSB Collaborative Curriculum Development Program 2016 Learning Objectives • Energy in Biology • Insulin Signaling • Insulin Resistance and Type 2 Diabetes Developed as part of the RCSB Collaborative Curriculum Development Program 2016 Learning Objectives • Energy in Biology • Insulin Signaling • Insulin Resistance and Type 2 Diabetes Developed as part of the RCSB Collaborative Curriculum Development Program 2016 Energy in Biology • ATP: Energy currency of cells • Main sources of ATP Glycogen Amino acids; Glycerol etc. ----Adenine-----Adenosine--------------Adenosine monophosphate(AMP) ----Adenosine diphosphate(ADP)-----------Adenosine triphosphate(ATP)--------------- Substrate Product Metabolic Process Glucose Pyruvate Glycolysis Pyruvate Acetyl CoA Pyruvate Dehydrogenase Acetyl CoA CO2 Kreb’s Cycle Free fatty acids Acetyl CoA Beta oxidation Fats Developed as part of the RCSB Collaborative Curriculum Development Program 2016 Glucose Homeostasis • Pancreas produces – Insulin • Produced by b cells • Promotes uptake of glucose from plasma – Glucagon • Produced by a cells • Promotes processes to release glucose into plasma Developed as part of the RCSB Collaborative Curriculum Development Program 2016 Balancing Insulin and Glucagon Incretins GLP-1; GIP (Gut cells) Insulin production – High blood glucose – Glucagon – Incretin hormones • Glucose-dependent insulinotropic peptide (GIP) • Glucagon-like-peptide 1 (GLP-1) Glucagon production Insulin (b cells) Glucagon (a cells) – Low blood glucose – Insulin Developed as part of the RCSB Collaborative Curriculum Development Program 2016 Somatostatin (d cells) Glucose Transporters 14 Types known; GLUT 1-4 characterized • • GLUT1 – Main transporter in red blood cells and blood-tissue barriers – Ubiquitous; medium affinity – For basal-level glucose uptake • Glucose Co-transporters – Sodium Glucose co-transporters (SGLTs) GLUT2 – Allows uptake and efflux of glucose in response to fed or fasted state – Mediates transport in liver, intestinal, kidney and pancreatic cells – Low affinity • GLUT3 – Primary function in neurons, and circulating white blood cells – High affinity • GLUT4 – Responsive to insulin – In adipocytes and muscle (skeletal and cardiac) cells http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104978/figure/F6/ Developed as part of the RCSB Collaborative Curriculum Development Program 2016 http://www.nature.com/nature/journal/v526/n7573/full/nature14655.html Transporter GLUT3 in Action Movie at http://www.nature.com/natu re/journal/v526/n7573/fig_t ab/nature14655_SV3.html Developed as part of the RCSB Collaborative Curriculum Development Program 2016 Learning Objectives • Energy in Biology • Insulin Signaling • Insulin Resistance and Type 2 Diabetes Developed as part of the RCSB Collaborative Curriculum Development Program 2016 Insulin Signaling Insulin Receptor Insulin Insulin-Insulin Receptor Complex Extra-cellular Transmembrane Cytoplasmic http://pdb101.rcsb.org/motm/182 Developed as part of the RCSB Collaborative Curriculum Development Program 2016 Insulin Receptor Insulin Receptor L2 FnIII-1 L1 aCT FnIII-2 CR Extra-cellular FnIII-3 Transmembrane Cytoplasmic http://pdb101.rcsb.org/motm/182 http://www.ncbi.nlm.nih.gov/pmc/articl es/PMC3793637/ Developed as part of the RCSB Collaborative Curriculum Development Program 2016 Ecto IR, PDB ID 3loh Insulin Binding to Receptor Insulin-Insulin Receptor Complex Ins:mIR complex, PDB ID 3w14 a-CT of second IR protein interacts with insulin and first IR molecule http://pdb101.rcsb.org/motm/182 Developed as part of the RCSB Collaborative Curriculum Development Program 2016 Insulin Signal Transduction • IR Tyrosine Kinase domain: – Inactive state (PDB ID 1irk) a mobile loop blocks entry of substrate – Active state (PDB ID 1ir3) several tyrosines on this loop are phosphorylated, loop swings out of active site, allowing ATP and other signaling proteins to bind. – Active site uses ATP to phosphorylate its targets. Tyrosine Kinase domain of IR showing inactive (PDB ID 1IRK) and active (PDB IDs 1IR3) forms Insulin Signaling 1. Insulin binds 6. Protein Synthesis 7. Cell Survival 8. Proliferation 2. Tyrosine Kinase activation 4. Translocate GLUT4 transporters 5. Glucose uptake Metabolism 3. Signaling molecules: IRS, PI3K, PDK1, AKT, AS160 etc. Glycolysis ATP + Pyruvate Lipogenesis Lipids Developed as part of the RCSB Collaborative Curriculum Development Program 2016 Storage Glycogenesis glycogen Insulin Signal Transduction PIP2 IRS P PIP3 PI3K P PKC Translocate to Glucose uptake PDK1 Glycogen Synthesis P GSK3 Gluconeogenesis FOXO1 Protein Synthesis mTORC1 AKT2 P AS160 P mTORC2 Developed as part of the RCSB Collaborative Curriculum Development Program 2016 GLUT4 vesicle Insulin Signal Transduction PIP2 IRS P PIP3 PI3K P PKC PDK1 PTP1B Glycogen Synthesis PTEN P GSK3 Glyconeogenesis FOXO1 Protein Synthesis mTORC1 AKT2 Translocate to Glucose uptake P AS160 P mTORC2 Developed as part of the RCSB Collaborative Curriculum Development Program 2016 GLUT4 vesicle Understanding AKT P AKT2 P • N-terminal PH domain localizes AKT to plasma membrane (levels of PI(3,4,5)P3 or PI(3,4)P2) • Catalytic domain activated by phosphorylation of Thr – T309 by PDK and S474 by mTORC1 AKT Kinase domain showing inactive (PDB ID 1MRV) and active (PDB IDs 1O6L) forms Learning Objectives • Energy in Biology • Insulin Signaling • Insulin Resistance and Type 2 Diabetes Developed as part of the RCSB Collaborative Curriculum Development Program 2016 Insulin Resistance • Insulin is present but signaling is disrupted at the level of IRS, AKT, AS160, etc. • Body tries to compensate by making more insulin PIP2 IRS P PIP3 PI3K P PKC Glucose uptake PDK1 Glycogen Synthesis P GSK3 Glyconeogenesis FOXO1 Protein Synthesis mTOR AKT2 P AS160 P mTOR/ Developed as part of the RCSB Collaborative Curriculum Development Program 2016 GLUT4 vesicle A Case of Insulin Resistance • A family with severe insulin resistance and diabetes due to a mutation in AKT2 Science. 2004 May 28; 304:1325-8. • Molecular Exploration … (see hands-on exercise attached) What May Happen in R274H Active Site Residues R274 Substrate peptide PDB ID 1o6l, Yang et al., 2002 TPO 309 Mutation of Arg 274 to His would disrupt the H-bonds holding the activation loop in the active state Summary • Energy in Biology – ATP is energy currency • Insulin Signaling – Reception, Signal Transduction and Response • Insulin Resistance and Type 2 Diabetes – Mutations may disrupt proteins in Insulin signaling Developed as part of the RCSB Collaborative Curriculum Development Program 2016