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RATIONAL DESIGN OF A CALCIUM-BINDING ADHESION PROTEIN NMR, 20 STRUCTURES

Overview

Ca2+, "a signal of life and death", controls numerous cellular processes, through interactions with proteins. An effective approach to understanding, the role of Ca2+ is the design of a Ca2+-binding protein with predicted, structural and functional properties. To design de novo Ca2+-binding sites, in proteins is challenging due to the high coordination numbers and the, incorporation of charged ligand residues, in addition to Ca2+-induced, conformational change. Here, we demonstrate the successful design of a, Ca2+-binding site in the non-Ca2+-binding cell adhesion protein CD2. This, designed protein, Ca.CD2, exhibits selectivity for Ca2+ versus other di-, and monovalent cations. In addition, La3+ (Kd 5.0 microM) and Tb3+ (Kd 6.6, microM) bind to the designed protein somewhat more tightly than does Ca2+, (Kd 1.4 mM). More interestingly, Ca.CD2 retains the native ability to, associate with the natural target molecule. The solution structure reveals, that Ca.CD2 binds Ca2+ at the intended site with the designed arrangement, which validates our general strategy for designing de novo Ca2+-binding, proteins. The structural information also provides a close view of, structural determinants that are necessary for a functional protein to, accommodate the metal-binding site. This first success in designing, Ca2+-binding proteins with desired structural and functional properties, opens a new avenue in unveiling key determinants to Ca2+ binding, the, mechanism of Ca2+ signaling, and Ca2+-dependent cell adhesion, while, avoiding the complexities of the global conformational changes and, cooperativity in natural Ca2+-binding proteins. It also represents a major, achievement toward designing functional proteins controlled by Ca2+, binding.

About this Structure

1T6W is a Single protein structure of sequence from Rattus norvegicus with CA as ligand. Full crystallographic information is available from OCA.

Reference

Design of a calcium-binding protein with desired structure in a cell adhesion molecule., Yang W, Wilkins AL, Ye Y, Liu ZR, Li SY, Urbauer JL, Hellinga HW, Kearney A, van der Merwe PA, Yang JJ, J Am Chem Soc. 2005 Feb 23;127(7):2085-93. PMID:15713084

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