Molecular basis for the interaction between human choline kinase alpha and the SH3 domain of the c-Src tyrosine kinase

Kall, Stefanie L.; Whitlatch, Kindra; Smithgall, Thomas E.; Lavie, Arnon

doi:10.1038/s41598-019-53447-0

Title: Molecular basis for the interaction between human choline kinase alpha and the SH3 domain of the c-Src tyrosine kinase

Journal Article · Tue Nov 19 00:00:00 EST 2019 · Scientific Reports

DOI:https://doi.org/10.1038/s41598-019-53447-0· OSTI ID:1578228

Kall, Stefanie L. ^[1]; Whitlatch, Kindra ^[2]; Smithgall, Thomas E. ^[2]; Lavie, Arnon ^[3]

Univ. of Illinois, Chicago, IL (United States)
University of Pittsburgh School of Medicine, PA (United States)
Univ. of Illinois, Chicago, IL (United States); Jesse Brown VA Medical Center, Chicago, IL (United States)

Choline kinase alpha is a 457-residue protein that catalyzes the reaction between ATP and choline to yield ADP and phosphocholine. This metabolic action has been well studied because of choline kinase’s link to cancer malignancy and poor patient prognosis. As the myriad of x-ray crystal structures available for this enzyme show, chemotherapeutic drug design has centered on stopping the catalytic activity of choline kinase and reducing the downstream metabolites it produces. Furthermore, these crystal structures only reveal the catalytic domain of the protein, residues 80–457. However, recent studies provide evidence for a non-catalytic protein-binding role for choline kinase alpha. Here, we show that choline kinase alpha interacts with the SH3 domain of c-Src. Co-precipitation assays, surface plasmon resonance, and crystallographic analysis of a 1.5 Å structure demonstrate that this interaction is specific and is mediated by the poly-proline region found N-terminal to the catalytic domain of choline kinase. Taken together, these data offer strong evidence that choline kinase alpha has a heretofore underappreciated role in protein-protein interactions, which offers an exciting new way to approach drug development against this cancer-enhancing protein.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH); US Department of Veteran Affairs; National Institute of Dental and Craniofacial Research (NIDCR); National Institute of General Medical Sciences (NIGMS); Michigan Economic Development Corporation; Michigan Technology Tri-Corridor

Grant/Contract Number:: AC02-06CH11357; R01EB013685; I01BX001919; DE018381; GM088119; 085P1000817

OSTI ID:: 1578228

Journal Information:: Scientific Reports, Vol. 9, Issue 1; ISSN 2045-2322

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 5 works

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Title: Molecular basis for the interaction between human choline kinase alpha and the SH3 domain of the c-Src tyrosine kinase

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