Resurgence of phosphotyrosine binding domains: Structural and functional properties essential for understanding disease pathogenesis

Abstract

Background: Phosphotyrosine Binding (PTB) Domains, usually found on scaffold proteins, are pervasive in many cellular signaling pathways. These domains are the second-largest family of phosphotyrosine recognition domains and since their initial discovery, dozens of PTB domains have been structurally determined.

Scope of review: Due to its signature sequence flexibility, PTB domains can bind to a large variety of ligands including phospholipids. PTB peptide binding is divided into classical binding (canonical NPXY motifs) and non-classical binding (all other motifs). The first atypical PTB domain was discovered in cerebral cavernous malformation 2 (CCM2) protein, while only one third in size of the typical PTB domain, it remains functionally equivalent.

Major conclusions: PTB domains are involved in numerous signaling processes including embryogenesis, neurogenesis, and angiogenesis, while dysfunction is linked to major disorders including diabetes, hypercholesterolemia, Alzheimer's disease, and strokes. PTB domains may also be essential in infectious processes, currently responsible for the global pandemic in which viral cellular entry is suspected to be mediated through PTB and NPXY interactions.

General significance: We summarize the structural and functional updates in the PTB domain over the last 20 years in hopes of resurging interest and further analyzing the importance of this versatile domain.

Keywords: Atypical PTB (aPTB) domains; Classical PTB domain binding motifs (CPBM); Non-classical PTB domain binding motifs (NPBM); Phosphotyrosine binding (PTB) domain.