A Mechanism for Tunable Autoinhibition in the Structure of a Human Ca2+/Calmodulin-Dependent Kinase II Holoenzyme

被引：201

作者：

Chao, Luke H. ^{[1
,2
,3
,4
]}

Stratton, Margaret M. ^{[1
,2
,3
,4
]}

Lee, Il-Hyung ^{[2
,3
,4
]}

Rosenberg, Oren S. ^{[1
,2
,3
,4
]}

Levitz, Joshua ^{[5
]}

Mandell, Daniel J. ^{[6
,7
]}

Kortemme, Tanja ^{[6
,7
]}

Groves, Jay T. ^{[2
,3
,4
,5
,9
,10
]}

Schulman, Howard ^{[8
]}

Kuriyan, John ^{[1
,2
,3
,4
,5
,10
]}

机构：

[1] Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA

[2] Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA

[3] Univ Calif Berkeley, Calif Inst Quantitat Biosci QB3, Berkeley, CA 94720 USA

[4] Univ Calif Berkeley, Howard Hughes Med Inst, Berkeley, CA 94720 USA

[5] Univ Calif Berkeley, Biophys Grad Grp, Berkeley, CA 94720 USA

[6] Univ Calif San Francisco, Calif Inst Quantitat Biosci QB3, San Francisco, CA 94143 USA

[7] Univ Calif San Francisco, Dept Bioengn & Therapeut Sci, San Francisco, CA 94143 USA

[8] Allosteros Therapeut, Sunnyvale, CA 94089 USA

[9] Univ Calif Berkeley, Lawrence Berkeley Lab, Div Mat Sci, Berkeley, CA 94720 USA

[10] Univ Calif Berkeley, Lawrence Berkeley Lab, Phys Biosci Div, Berkeley, CA 94720 USA

来源：

CELL | 2011年 / 146卷 / 05期

关键词：

DEPENDENT PROTEIN-KINASE; RAY SOLUTION SCATTERING; CAM KINASE; INHIBITORY AUTOPHOSPHORYLATION; CA2+ OSCILLATIONS; IN-VITRO; CALMODULIN; ACTIVATION; ALPHA; BRAIN;

D O I：

10.1016/j.cell.2011.07.038

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Calcium/calmodulin-dependent kinase II (CaMKII) forms a highly conserved dodecameric assembly that is sensitive to the frequency of calcium pulse trains. Neither the structure of the dodecameric assembly nor how it regulates CaMKII are known. We present the crystal structure of an autoinhibited full-length human CaMKII holoenzyme, revealing an unexpected compact arrangement of kinase domains docked against a central hub, with the calmodulin-binding sites completely inaccessible. We show that this compact docking is important for the autoinhibition of the kinase domains and for setting the calcium response of the holoenzyme. Comparison of CaMKII isoforms, which differ in the length of the linker between the kinase domain and the hub, demonstrates that these interactions can be strengthened or weakened by changes in linker length. This equilibrium between autoinhibited states provides a simple mechanism for tuning the calcium response without changes in either the hub or the kinase domains.

引用

页码：732 / 745

页数：14

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