1y6w

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Revision as of 18:09, 12 November 2007

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spinqualitylabelsall models 1y6w, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

Trapped intermediate of calmodulin

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Calmodulin (CaM) is a multifunctional Ca2+-binding protein that regulates, the activity of many enzymes in response to changes in the intracellular, Ca2+ concentration. There are two globular domains in CaM, each containing, a pair of helix-loop-helix Ca2+-binding motifs called EF-hands., Ca2+-binding induces the opening of both domains thereby exposing, hydrophobic pockets that provide binding sites for the target enzymes., Here, I present a 2.4 A resolution structure of a calmodulin mutant, (CaM41/75) in which the N-terminal domain is locked in the closed, conformation by a disulfide bond. CaM41/75 crystallized in a tetragonal, lattice with the Ca2+ bound in all four EF-hands. In the closed N-terminal, domain Ca ions are coordinated by the four protein ligands in positions 1, 3, 5 and 7 of the loop, and by two solvent ligands. The glutamate, side-chain in the 12th position of the loop (Glu31 in site I and Glu67 in, site II), which in the wild-type protein provides a bidentate Ca2+ ligand, remains in a distal position. Based on a comparison of CaM41/75 with other, CaM and troponin C structures a detailed two-step mechanism of the, Ca2+-binding process is proposed. Initially, the Ca2+ binds to the, N-terminal part of the loop, thus generating a rigid link between the, incoming helix (helix A, or helix C) and the central beta structure, involving the residues in the sixth, seventh and eighth position of the, loop. Then, the exiting helix (helix B or helix D) rotates causing the, glutamate ligand in the 12th position to move into the vicinity of the, immobilized Ca2+. An adjustment of the phi, psi backbone dihedral angles, of the Ile residue in the eighth position is necessary and sufficient for, the helix rotation and functions as a hinge. The model allows for a, significant independence of the Ca2+-binding sites in a two-EF-hand, domain.

Disease

Known diseases associated with this structure: Cavernous malformations of CNS and retina OMIM:[604214], Cerebral cavernous malformations-1 OMIM:[604214], Hyperkeratotic cutaneous capillary-venous malformations associated with cerebral capillary malformations OMIM:[604214], Leukemia, acute T-cell lymphoblastic OMIM:[603025], Leukemia, acute myeloid OMIM:[603025]

About this Structure

1Y6W is a Single protein structure of sequence from Homo sapiens with CA, MPD and TBU as ligands. Full crystallographic information is available from OCA.

Reference

Structure of a trapped intermediate of calmodulin: calcium regulation of EF-hand proteins from a new perspective., Grabarek Z, J Mol Biol. 2005 Mar 11;346(5):1351-66. Epub 2005 Jan 19. PMID:15713486

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