Regulation of intrasteric inhibition of the multifunctional calcium/calmodulin-dependent protein kinase

Francisco H. Cruzalegui, Michael S Kapiloff, John Paul Morfin, Bruce E. Kemp, Michael G. Rosenfeld, Anthony R. Means

Research output: Contribution to journalArticle

75 Citations (Scopus)

Abstract

A regulatory region involved in both autoinhibition and calmodulin (CaM) binding has previously been identified in the multifunctional Ca2+/CaM-dependent protein kinase (CaM kinase II). We have tested the role of various segments of the regulatory region in autoinhibition by the analysis of a series of truncation, substitution, and deletion mutants of the CaM kinase II α subunit (CaM kinase IIα). Unexpectedly, the sequence Lys-Lys-Phe-Asn at positions 291-294, adjacent to the CaM binding domain, was found to be sufficient to maintain an inhibited state in a truncated form of the kinase. However, these residues are not essential in the context of the full-length protein, indicating the importance of additional residues from the overlapping CaM binding domain. We propose here a molecular model for CaM kinase IIα based on the three-dimensional structure of the cAPK-PKI-(5-24) (protein kinase inhibitor fragment) complex. It is predicted from this model that autoinhibition is of the pseudosubstrate variety and that autophosphorylation of Thr-286 could occur by an intersubunit reaction in the holoenzyme complex.

Original languageEnglish
Pages (from-to)12127-12131
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume89
Issue number24
StatePublished - Dec 1 1992
Externally publishedYes

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Calcium-Calmodulin-Dependent Protein Kinases
Calmodulin
Nucleic Acid Regulatory Sequences
Holoenzymes
Molecular Models
Protein Kinase Inhibitors
Phosphotransferases
Proteins

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Cruzalegui, F. H., Kapiloff, M. S., Morfin, J. P., Kemp, B. E., Rosenfeld, M. G., & Means, A. R. (1992). Regulation of intrasteric inhibition of the multifunctional calcium/calmodulin-dependent protein kinase. Proceedings of the National Academy of Sciences of the United States of America, 89(24), 12127-12131.

Regulation of intrasteric inhibition of the multifunctional calcium/calmodulin-dependent protein kinase. / Cruzalegui, Francisco H.; Kapiloff, Michael S; Morfin, John Paul; Kemp, Bruce E.; Rosenfeld, Michael G.; Means, Anthony R.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 89, No. 24, 01.12.1992, p. 12127-12131.

Research output: Contribution to journalArticle

Cruzalegui, FH, Kapiloff, MS, Morfin, JP, Kemp, BE, Rosenfeld, MG & Means, AR 1992, 'Regulation of intrasteric inhibition of the multifunctional calcium/calmodulin-dependent protein kinase', Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 24, pp. 12127-12131.
Cruzalegui, Francisco H. ; Kapiloff, Michael S ; Morfin, John Paul ; Kemp, Bruce E. ; Rosenfeld, Michael G. ; Means, Anthony R. / Regulation of intrasteric inhibition of the multifunctional calcium/calmodulin-dependent protein kinase. In: Proceedings of the National Academy of Sciences of the United States of America. 1992 ; Vol. 89, No. 24. pp. 12127-12131.
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