2hf5

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The structure and function of a novel two-site calcium-binding fragment of calmodulin

Contents 1 Overview 2 Disease 3 About this Structure 4 Reference

Overview

Calmodulin (CaM) is an EF-hand protein composed of two calcium, (Ca(2+))-binding EF-hand motifs in its N-domain (EF-1 and EF-2) and two in, its C-domain (EF-3 and EF-4). In this study, we examined the structure, dynamics, and Ca(2+)-binding properties of a fragment of CaM containing, only EF-2 and EF-3 and the intervening linker sequence (CaM2/3). Based on, NMR spectroscopic analyses, Ca(2+)-free CaM2/3 is predominantly unfolded, but upon binding Ca(2+), adopts a monomeric structure composed of two, EF-hand motifs bridged by a short antiparallel beta-sheet. Despite having, an "even-odd" pairing of EF-hands, the tertiary structure of CaM2/3 is, similar to both the "odd-even" paired N- and C-domains of Ca(2+)-ligated, CaM, with the conformationally flexible linker sequence adopting the role, of an inter-EF-hand loop. However, unlike either CaM domain, CaM2/3, exhibits stepwise Ca(2+) binding with a K (d1) = 30 +/- 5 muM to EF-3, and, a K (d2) > 1000 muM to EF-2. Binding of the first equivalent of Ca(2+), induces the cooperative folding of CaM2/3. In the case of native CaM, stacking interactions between four conserved aromatic residues help to, hold the first and fourth helices of each EF-hand domain together, while, the loop between EF-hands covalently tethers the second and third helices., In contrast, these aromatic residues lie along the second and third, helices of CaM2/3, and thus are positioned adjacent to the loop between, its "even-odd" paired EF-hands. This nonnative hydrophobic core packing, may contribute to the weak Ca(2+) affinity exhibited by EF-2 in the, context of CaM2/3.

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

2HF5 is a Single protein structure of sequence from Homo sapiens with CA as ligand. Full crystallographic information is available from OCA.

Reference

Calcium-induced folding of a fragment of calmodulin composed of EF-hands 2 and 3., Lakowski TM, Lee GM, Okon M, Reid RE, McIntosh LP, Protein Sci. 2007 Jun;16(6):1119-32. Epub 2007 May 1. PMID:17473011

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