Decoding WW Domain Tandem-mediated Target Recognitions in Tissue Growth and Cell Polarity

Abstract

WW domain tandem-containing proteins such as KIBRA, YAP, and MAGI play critical roles in cell growth and polarity via binding to and positioning target proteins in specific subcellular regions. An immense disparity exists between promiscuity of WW domain-mediated target bindings and specific roles of WW domain scaffold proteins in cell growth regulation. Here, we discovered that WW domain tandems of KIBRA and MAGI, but not YAP, bind to specific target proteins with extremely high affinity and exquisite specificity. Via systematic structural biology and biochemistry approaches, we decoded the target binding rules of WW domain tandems from cell growth regulatory proteins and uncovered a list of previously unknown WW tandem binding proteins such as β-Dystroglycan, JCAD, and PTPN21. The WW tandemmediated target recognition mechanisms elucidated here can guide functional studies of WW domain proteins in cell growth and polarity as well as in other cellular processes including neuronal synaptic signaling.

A Conserved Amino Acid in the C Terminus of Human Papillomavirus E7 Mediates Binding to PTPN14 and Repression of Epithelial Differentiation

“…PTPN14 is proposed to inhibit the HIPPO pathway transcriptional coactivators YAP1 and TAZ. The inhibitory activity of PTPN14 may involve interaction(s) with the HIPPO pathway regulators KIBRA and LATS1 (31)(32)(33) and/or direct binding of PTPN14 to YAP1, promoting YAP1 cytoplasmic sequestration (34). PTPN14 phosphatase activity is not required for its inhibition of YAP1.…”

Interactions between AMOT PPxY motifs and NEDD4L WW domains function in HIV-1 release

“…The model suggests that formation of a stable NEDD4L WW3/WW4 interdomain interface may be disfavored by the anionic Glu 526 residue located between the WW3 and WW4 domains (replacing Ile 35 in the equivalent position of KIBRA WW1/WW2). Consistent with this idea, the affinity of the KIBRA-AMOT complex is reduced 50-fold when Ile 35 is mutated to Asp (34). Cooperative binding may also be disfavored by substitution of two other large hydrophobic KIBRA WW1/WW2 interface residues (Phe 47 and Leu 57 ) with smaller hydrophobics at equivalent positions in NEDD4L WW3/WW4 (Leu 542 and Pro 552 , respectively).…”

“…To understand why the KIBRA WW1/WW2 element binds tightly to AMOT, whereas the similarly spaced, tandem NEDD4L WW3/WW4 element does not, we modeled NEDD4L WW3/WW4 based on the KIBRA WW1/WW2 structure ( 34 ) ( Fig. S1 ).…”