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UniProtKB/Swiss-Prot variant pages

UniProtKB/Swiss-Prot P35568: Variant p.Ala512Pro

Insulin receptor substrate 1
Gene: IRS1
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Variant information Variant position: help 512
Type of variant: help LB/B
Residue change: help From Alanine (A) to Proline (P) at position 512 (A512P, p.Ala512Pro).
Physico-chemical properties: help Change from small size and hydrophobic (A) to medium size and hydrophobic (P)
BLOSUM score: help -1
Polymorphism: help The Arg-971 polymorphism impairs the ability of insulin to stimulate glucose transport, glucose transporter translocation, and glycogen synthesis by affecting the PI3K/AKT1/GSK3 signaling pathway. The polymorphism at Arg-971 may contribute to the in vivo insulin resistance observed in carriers of this variant. Arg-971 could contribute to the risk for atherosclerotic cardiovascular diseases associated with non-insulin-dependent diabetes mellitus (NIDDM) by producing a cluster of insulin resistance-related metabolic abnormalities. In insulin-stimulated human endothelial cells from carriers of the Arg-971 polymorphism, genetic impairment of the IRS1/PI3K/PDPK1/AKT1 insulin signaling cascade results in impaired insulin-stimulated nitric oxide (NO) release and suggested that this may be a mechanism through which the Arg-971 polymorphism contributes to the genetic predisposition to develop endothelial dysfunction and cardiovascular disease. The Arg-971 polymorphism not only reduces phosphorylation of the substrate but allows IRS1 to act as an inhibitor of PI3K, producing global insulin resistance.
Other resources: help


Sequence information Variant position: help 512
Protein sequence length: help 1242
Location on the sequence: help HRCTPGTGLGTSPALAGDEA A SAADLDNRFRKRTHSAGTSP
Residue conservation: help
Human                         HRCTPGTGLGTSPALAGDEAASAADL--DNRFRKRTHSAGTSP

Mouse                         HRYIPGANLGTSPALPGDEAAGAADL--DNRFRKRTHSAGT

Rat                           HRYIPGATMGTSPALTGDEAAGAADL--DNRFRKRTHSAGT

Xenopus tropicalis            ----------------------------------------M

Drosophila                    SLHF------NFPEHASEKLAKDFDLDSDNQCCRPIRAYSI

Sequence annotation in neighborhood: help
TypePositionsDescription
Chain 1 – 1242 Insulin receptor substrate 1
Modified residue 527 – 527 Phosphoserine; by RPS6KB1
Mutagenesis 527 – 527 S -> A. Impaired degradation by the Cul7-RING(FBXW8) complex; when associated with A-307; A-312; A-636 and A-639.



Literature citations
Aminoacid polymorphisms of insulin receptor substrate-1 in non-insulin-dependent diabetes mellitus.
Almind K.; Bjoerbaek C.; Vestergaard H.; Hansen T.; Echwald S.; Pedersen O.;
Lancet 342:828-832(1993)
Cited for: VARIANTS PRO-512 AND ARG-971;
Disclaimer: Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. They are not in any way intended to be used as a substitute for professional medical advice, diagnostic, treatment or care.