Abstract
In the endoplasmic reticulum, calreticulin acts as a chaperone and a Ca2+-signalling protein. At the cell surface, it mediates numerous important biological effects. The crystal structure of the human calreticulin globular domain was solved at 1.55 Å resolution. Interactions of the flexible N-terminal extension with the edge of the lectin site are consistently observed, revealing a hitherto unidentified peptide-binding site. A calreticulin molecular zipper, observed in all crystal lattices, could further extend this site by creating a binding cavity lined by hydrophobic residues. These data thus provide a first structural insight into the lectin-independent binding properties of calreticulin and suggest new working hypotheses, including that of a multi-molecular mechanism.
Highlights
Calreticulin (CRT) is an intriguing multi-compartmental protein involved in many cellular processes with broad pathophysiological implications [1,2]
Several independent serendipitous observations lead to the first description of unfolded protein segments bound to CRT, on the outer edge of the lectin site
Further investigations of the binding specificity of this area might be possible by designing the sequence of the N-terminal extension of CRT
Summary
Calreticulin (CRT) is an intriguing multi-compartmental protein involved in many cellular processes with broad pathophysiological implications [1,2]. The molecular and structural determinants involved in these various CRT properties still need to be deciphered, except for the lectin binding site [9]. The pioneering crystallographic analysis of a large fragment from CNX has revealed an extended P-domain inserted into a globular legume lectin-like domain [10], but available structural data for CRT have long been restricted to the NMR structure of its P-domain [11]. Careful analysis of the crystal packing interactions reveals that the disordered Nterminal extension binds to the edge of the lectin site and that an intriguing CRT molecular zipper could provide a larger binding platform. These observations provide a new structural basis for the non-lectin chaperone activity of CRT
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