Membrane BindingC2‐Like Domains

Abstract

C2‐domains are independently folded modules, of about 130 residues, found in a large and diverse set of eukaryotic proteins. Many of the best‐characterized C2‐domains are found in proteins involved in membrane trafficking and fusion, such as synaptotagmins or rabphilin, and in signal transduction, such as phospholipases A2 (cPLA2) and C (PLC) or the protein kinase C isoforms (PKCs). All C2‐domains share a common overall fold: a single compact Greek‐key motif organized as an eight‐stranded antiparallel β‐sandwich consisting of a pair of four‐stranded β‐sheets – the A and B sheets – with a long axis of about 50 Å. Connections between β‐strands emerge from the top and bottom of the domain according to the two distinct topologies of C2‐domains. In topology I (the S family), the first β‐strand occupies the same structural position as the eighth β‐strand of topology II (the P family), which shifts in a circular permutation the order of homologous strands in the primary structure. The structural information defines adjacent calcium binding sites within a broad acidic cleft that contains highly conserved acidic residues. These provide most of the oxygen atoms that coordinate with the calcium ions. The present work will focus on the wealth of functional and structural information, which is being obtained at an exponential pace, on the membrane‐binding C2‐domains that require calcium.

The C2 Domains of Classical PKCs are Specific PtdIns(4,5)P2-sensing Domains with Different Affinities for Membrane Binding

“…14-17 C2 domains share a common overall fold: a single compact Greek-key motif organized as an eight-stranded antiparallel β-sandwich with flexible loops on the top and on the bottom, although not all of them are able to bind Ca 2+ . 14,15,17,18 In classical PKCs, C2 domains display two functional motifs. The first is the Ca 2+ -binding region, located in the flexible top loops, that binds two or three calcium ions, depending on the isoenzyme, [19][20][21][22][23][24][25] and interacts with phosphatidylserine ( Figure 1).…”