Identification of residues involved in allosteric signal transmission from amino acid binding site of pyruvate kinase muscle isoform 2

Suparno Nandi; Mishtu Dey

doi:10.1371/journal.pone.0282508

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Identification of residues involved in allosteric signal transmission from amino acid binding site of pyruvate kinase muscle isoform 2

Journal article

Open access

Peer reviewed

Identification of residues involved in allosteric signal transmission from amino acid binding site of pyruvate kinase muscle isoform 2

Suparno Nandi and Mishtu Dey

PloS one, Vol.18(3), e0282508

03/10/2023

DOI: 10.1371/journal.pone.0282508

PMCID: PMC10004559

PMID: 36897854

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Abstract

PKM2 is a rate-limiting enzyme in the glycolytic process and is involved in regulating tumor proliferation. Several amino acids (AAs) such as Asn, Asp, Val, and Cys have been shown to bind to the AA binding pocket of PKM2 and modulate its oligomeric state, substrate binding affinity, and activity. Although previous studies have attributed that the main chain and side chain of bound AAs are responsible for initiating signal to regulate PKM2, the signal transduction pathway remains elusive. To identify the residues involved in signal transfer process, N70 and N75 located at two ends of a β strand connecting the active site and AA binding pocket were altered. Biochemical studies of these variants with various AA ligands (Asn, Asp, Val, and Cys), illustrate that N70 and N75, along with β1 connecting these residues are part of the signal transduction pathway between the AA binding pocket and the active site. The results demonstrate that mutation of N70 to D prevents the transfer of the inhibitory signal mediated by Val and Cys, whereas N75 to L alteration blocks the activating signal initiated by Asn and Asp. Taken together, this study confirms that N70 is one of the residues responsible for transmitting the inhibitory signal and N75 is involved in the activation signal flow.

Signal Transduction

Amino Acids - metabolism

Catalytic Domain

Humans

Protein Isoforms - metabolism

Pyruvate Kinase - chemistry

Pyruvate Kinase - metabolism

Details

Title: Subtitle: Identification of residues involved in allosteric signal transmission from amino acid binding site of pyruvate kinase muscle isoform 2
Creators: Suparno Nandi - University of Iowa
Mishtu Dey - University of Iowa, Chemistry
Resource Type: Journal article
Publication Details: PloS one, Vol.18(3), e0282508
DOI: 10.1371/journal.pone.0282508
PMID: 36897854
PMCID: PMC10004559
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Grant note: DOI: 10.13039/100000001, name: National Science Foundation, award: CLP 1506181
Language: English
Date published: 03/10/2023
Academic Unit: Chemistry
Record Identifier: 9984473218302771

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