Mining for allosteric information: natural mutations and positional sequence conservation in pyruvate kinase.

Abstract:

:Although the amino acid sequences and the structures of pyruvate kinase (PYK) isozymes are highly conserved, allosteric regulations differ. This suggests that amino acids with low conservation play important roles in the allosteric mechanism. The current work exploits a 'natural screen'- the 122 point mutations identified in the human gene encoding the erythrocyte PYK isozyme and associated with nonspherocytic hemolytic anemia - to learn what amino acid positions in PYK may be important for allosteric regulations. In addition to the mutations, we consider the conservation of each amino acid position across 241 PYK sequences. Three groups of residue positions have been created, those with: (1) no disease causing mutation identified; (2) a disease causing mutation identified and high conservation across isozymes; and (3) a disease causing mutation identified and low conservation. Mutations at positions not identified in the natural screen are likely to be tolerated with minimal loss of function. Mutations at highly conserved positions are more likely to disrupt properties common to all PYK isozymes (e.g., structure, catalysis). Residues in the third group are likely to be involved in roles that are necessary for function but not common to all isozymes (e.g., allostery). Many of the Group 3 residues are located in the C-domain and to a lesser extent the A domain.

journal_name

IUBMB Life

journal_title

IUBMB life

authors

Pendergrass DC,Williams R,Blair JB,Fenton AW

doi

10.1080/15216540500531705

keywords:

subject

Has Abstract

pub_date

2006-01-01 00:00:00

pages

31-8

issue

1

eissn

1521-6543

issn

1521-6551

pii

T46207Q641713UMJ

journal_volume

58

pub_type

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