Molecular model-building of amylin and alpha-calcitonin gene-related polypeptide hormones using a combination of knowledge sources.
Amylin is the major component of the amyloid found in the pancreases of noninsulin-dependent diabetics (type 2 diabetes). It is a 37 amino acid polypeptide and has been shown to have 46% sequence identity with the neuropeptide alpha-calcitonin gene-related peptide (alpha-CGRP). Both amylin and alpha-CGRP are known to be potent inhibitors of glycogen synthesis in stripped rat soleus muscle. Secondary structure prediction and tertiary structure model-building show the two polypeptides to have an alpha-helix/beta-strand motif similar to that observed in the insulin B-chain. The results have been supported by CD spectroscopy, although there is no sequence similarity between insulin and amylin/alpha-CGRP. Aggregation states have been predicted based on the dimeric and hexameric arrangements seen in porcine insulin. Rat and hamster amylin have a changed sequence motif in the beta-strand which results in lack of amyloid formation and type 2 diabetes. This, we propose, is caused by disruption of hydrogen bonding which prevents the formation of the dimer.
Saldanha
J
J
Biomedical Computing Unit, Imperial Cancer Research Fund, London, UK.
Mahadevan
D
D
D000465:Algorithms; D000595:Amino Acid Sequence; D000682:Amyloid / Q000737:chemistry*; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000737:chemistry*; D002942:Circular Dichroism; D006801:Humans; D007328:Insulin / Q000737:chemistry; D058228:Islet Amyloid Polypeptide; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D011487:Protein Conformation; D051381:Rats; D016415:Sequence Alignment; D012984:Software; D013552:Swine
D000682:Amyloid; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D010455:Peptides; D015740:Calcitonin Gene-Related Peptide