Insulin Signaling A Molecular View Shuchismita Dutta Ph
- Slides: 22
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 Co. A Pyruvate Dehydrogenase Acetyl Co. A CO 2 Kreb’s Cycle Free fatty acids Acetyl Co. A 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 • GLUT 1 • – 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) GLUT 2 – Allows uptake and efflux of glucose in response to fed or fasted state – Mediates transport in liver, intestinal, kidney and pancreatic cells – Low affinity • GLUT 3 – Primary function in neurons, and circulating white blood cells – High affinity • GLUT 4 – Responsive to insulin – In adipocytes and muscle (skeletal and cardiac) cells http: //www. ncbi. nlm. nih. gov/pmc/articles/PMC 4104978/figure/F 6/ Developed as part of the RCSB Collaborative Curriculum Development Program 2016
http: //www. nature. com/nature/journal/v 526/n 7573/full/nature 14655. html Transporter GLUT 3 in Action Movie at http: //www. nature. com/nat ure/journal/v 526/n 7573/fig_ tab/nature 14655_SV 3. 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 Receptor Complex Extra-cellular Transmembrane Cytoplasmic http: //pdb 101. rcsb. org/motm/182 Developed as part of the RCSB Collaborative Curriculum Development Program 2016
Insulin Receptor L 2 Fn. III-1 L 1 Fn. III-2 a. CT CR Extra-cellular Fn. III-3 Transmembrane Cytoplasmic http: //pdb 101. rcsb. org/motm/182 http: //www. ncbi. nlm. nih. gov/pmc/articl es/PMC 3793637/ Developed as part of the RCSB Collaborative Curriculum Development Program 2016 Ecto IR, PDB ID 3 loh
Insulin Binding to Receptor Insulin-Insulin Receptor Complex Ins: m. IR complex, PDB ID 3 w 14 http: //pdb 101. rcsb. org/motm/182 a-CT of second IR protein interacts with insulin and first IR molecule Developed as part of the RCSB Collaborative Curriculum Development Program 2016
Insulin Signal Transduction • IR Tyrosine Kinase domain: – Inactive state (PDB ID 1 irk) a mobile loop blocks entry of substrate – Active state (PDB ID 1 ir 3) 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 1 IRK) and active (PDB IDs 1 IR 3) forms
Insulin Signaling 1. Insulin binds 6. Protein Synthesis 7. Cell Survival 8. Proliferation 2. Tyrosine Kinase activation 3. Signaling molecules: IRS, PI 3 K, PDK 1, AKT, AS 160 etc. 4. Translocate GLUT 4 transporters 5. Glucose uptake Metabolism Glycolysis ATP + Pyruvate Lipogenesis Lipids Developed as part of the RCSB Collaborative Curriculum Development Program 2016 Storage Glycogenesis glycogen
Insulin Signal Transduction P PIP 2 IRS PI 3 K PIP 3 P PKC PDK 1 Glycogen Synthesis P GSK 3 Gluconeogenesis FOXO 1 Protein Synthesis m. TORC 1 AKT 2 Translocate to Glucose uptake P AS 160 P m. TORC 2 Developed as part of the RCSB Collaborative Curriculum Development Program 2016 GLUT 4 vesicle
Insulin Signal Transduction P PTP 1 B Glycogen Synthesis PIP 2 IRS PI 3 K PIP 3 P PTEN PKC PDK 1 P GSK 3 Glyconeogenesis FOXO 1 Protein Synthesis m. TORC 1 AKT 2 Translocate to Glucose uptake P AS 160 P m. TORC 2 Developed as part of the RCSB Collaborative Curriculum Development Program 2016 GLUT 4 vesicle
Understanding AKT P AKT 2 P • N-terminal PH domain localizes AKT to plasma membrane ( levels of PI(3, 4, 5)P 3 or PI(3, 4)P 2) • Catalytic domain activated by phosphorylation of Thr – T 309 by PDK and S 474 by m. TORC 1 AKT Kinase domain showing inactive (PDB ID 1 MRV) and active (PDB IDs 1 O 6 L) 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, AS 160, etc. • Body tries to compensate by making more insulin P PIP 2 IRS PI 3 K PIP 3 P PKC Glucose uptake PDK 1 Glycogen Synthesis P GSK 3 Glyconeogenesis FOXO 1 Protein Synthesis m. TOR AKT 2 P AS 160 P m. TOR/ Developed as part of the RCSB Collaborative Curriculum Development Program 2016 GLUT 4 vesicle
A Case of Insulin Resistance • A family with severe insulin resistance and diabetes due to a mutation in AKT 2 Science. 2004 May 28; 304: 1325 -8. • Molecular Exploration … (see hands-on exercise attached)
What May Happen in R 274 H Active Site Residues R 274 Substrate peptide PDB ID 1 o 6 l, 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
- Insulin and insulin receptor
- Effect of insulin on carbohydrate metabolism
- Anup dutta hcl
- Partha dutta rpi
- Prabal dutta
- Niloy dutta uconn
- Dipanwita dutta
- Dan nordquist wsu
- Dr s k dutta
- Insulin molecular formula
- Giant molecular structure vs simple molecular structure
- Melting and boiling point of oxygen
- Giant molecular structure vs simple molecular structure
- Autocrine and juxtacrine signaling
- Vehicle ground guide hand signals
- Use visual signaling techniques
- Most embryonic industries emerge from:
- Phosphorylation cascade
- 3 stages of cell communication
- Cell signaling overview
- Autocrine and juxtacrine signaling
- Cell communication types
- Chapter 48 neurons synapses and signaling