Allosteric activation of apicomplexan calcium-dependent protein kinases

Ingram, Jessica R.; Knockenhauer, Kevin E.; Markus, Benedikt M.; Mandelbaum, Joseph; Ramek, Alexander; Shan, Yibing; Shaw, David E.; Schwartz, Thomas U.; Ploegh, Hidde L.; Lourido, Sebastian

doi:10.1073/pnas.1505914112

Allosteric activation of apicomplexan calcium-dependent protein kinases

Journal Article · Mon Aug 24 00:00:00 EDT 2015 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1505914112· OSTI ID:1214843

Ingram, Jessica R. ^[1]; Knockenhauer, Kevin E. ^[2]; Markus, Benedikt M. ^[1]; Mandelbaum, Joseph ^[1]; Ramek, Alexander ^[3]; Shan, Yibing ^[3]; Shaw, David E. ^[4]; Schwartz, Thomas U. ^[2]; Ploegh, Hidde L. ^[5]; ^[1]

Whitehead Inst. for Biomedical Research, Cambridge, MA (United States)
Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States). Dept. of Biology
D. E. Shaw Research, New York, NY (United States)
D. E. Shaw Research, New York, NY (United States); Columbia Univ., New York, NY (United States). Dept. of Biochemistry and Molecular Biophysics
Whitehead Inst. for Biomedical Research, Cambridge, MA (United States); Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States). Dept. of Biology

Calcium-dependent protein kinases (CDPKs) comprise the major group of Ca²⁺-regulated kinases in plants and protists. It has long been assumed that CDPKs are activated, like other Ca²⁺-regulated kinases, by derepression of the kinase domain (KD). However, we found that removal of the autoinhibitory domain from Toxoplasma gondii CDPK1 is not sufficient for kinase activation. From a library of heavy chain-only antibody fragments (VHHs), we isolated an antibody (1B7) that binds TgCDPK1 in a conformation-dependent manner and potently inhibits it. We uncovered the molecular basis for this inhibition by solving the crystal structure of the complex and simulating, through molecular dynamics, the effects of 1B7–kinase interactions. In contrast to other Ca²⁺-regulated kinases, the regulatory domain of TgCDPK1 plays a dual role, inhibiting or activating the kinase in response to changes in Ca²⁺ concentrations. We propose that the regulatory domain of TgCDPK1 acts as a molecular splint to stabilize the otherwise inactive KD. This dependence on allosteric stabilization reveals a novel susceptibility in this important class of parasite enzymes.

View Accepted Manuscript (DOE)

Research Organization:: Whitehead Inst. for Biomedical Research, Cambridge, MA (United States)

Sponsoring Organization:: German Academic Exchange Service (Germany); National Inst. of Health (NIH) (United States); National Science Foundation (NSF) (United States); USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Contributing Organization:: Columbia Univ., New York, NY (United States); D. E. Shaw Research, New York, NY (United States); Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1214843

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Issue: 36 Vol. 112; ISSN 0027-8424

Publisher:: National Academy of Sciences, Washington, DC (United States)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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