WW Domains

WW domains contain ~ 40 amino acids with two invariant tryptophan residues (labeled W in single-letter amino acid code, hence the name WW domain) that bind to short proline-rich sequences containing PPXY, PPLP, or PPR motifs [47]. A small subclass of WW domains within the proline isomerases Pin1/Ess1 and their homologs, the splicing factor Prp40 and the ubiquitin ligase Rsp5, show specific binding to phosphoserine-proline motifs within mitotic phosphoproteins [48] and the phosphorylated C-terminal domain (CTD) of RNA polymerase II [49-51].

Phospho-specific WW domain function is best understood for the proline isomerase Pinl, a protein that slows progress through mitosis [52] but is also required for mitotic exit [53] and for the DNA replication checkpoint [53]. In addition to its WW domain, Pin1 contains a proline isomerase (rotamase) domain at its C terminus that catalyzes the specific cis-trans isomerization of pSer/Thr-Pro bonds [54,55]. Both the WW-domain-mediated pS-P binding and the rotamase-catalyzed pS-P isomerization are necessary for Pinl biological activity [53,56]. In addition, Pinl also enhances the dephosphorylation of substrates by protein phosphatases, all of which requires the pSer-Pro bond to be in trans. Because the WW domain can only bind to the trans geometric isomer, its major role may be to stabilize the trans-isomerase product for dephosphorylation [57,58]. WW-domain-facilitated substrate dephosphorylation is likely to be a general mechanism for WW domain function in both cell-cycle progression and regulation of transcriptional elongation.

WW domains fold into three anti-parallel P-strands, forming a single groove that recognizes proline-rich ligands in the context of a type II polyproline helix (Fig. 3). Specificity for different proline-rich motifs is determined largely by residues within the loop regions that connect the P1/P2 and P2/P3 strands, somewhat akin to the mechanism of ligand binding utilized by FHA domains. The structure of the Pinl WW domain in complex with a YpSPTpSPS

Figure 3 WW/phosphopeptide interactions. WW domains are named after two conserved Trp residues that form the structural core of the three-stranded domain (left panel). The pSer-Pro containing phosphopeptide (purple) derived from RNA polymerase II binds in an extended conformation across the P-sheet (right panel [59]). The oxygen atoms from only one of the two phosphates binds to residues located on the P1-P2 loop. Reprinted from Yaffe and Smerdon [75], with permission.

Figure 3 WW/phosphopeptide interactions. WW domains are named after two conserved Trp residues that form the structural core of the three-stranded domain (left panel). The pSer-Pro containing phosphopeptide (purple) derived from RNA polymerase II binds in an extended conformation across the P-sheet (right panel [59]). The oxygen atoms from only one of the two phosphates binds to residues located on the P1-P2 loop. Reprinted from Yaffe and Smerdon [75], with permission.

peptide from the CTD of RNA polymerase II [59] revealed that all of the phosphate contacts were made between the second pSer and two residues of the peptide in the P1/P2 loop (Ser-16 and Arg-17) along with one in the P2 strand (Tyr-23). These findings explain why only a few WW domains are competent to bind phosphorylated sequence motifs, as the majority of WW domains lack an Arg residue within loop 1 [59].

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