The Tax1 is a PDZ domain containing oncoprotein encoded by HTLV-1. [1]
Tax1 disrupts tumor suppressor pathways by using its PDZ-binding motif to interact with key scaffolding proteins such as Scribble and Erbin. [6] [7] [8]
Tax1 contains a conserved PDZ-binding motif at its C-terminus that allows it to bind multiple PDZ domains in host proteins. [8] [7] These interactions interfere with tumor suppressor functions, disrupting epithelial cell polarity through Scribble and enhancing growth signaling via Erbin. [6] [7] [8] By mimicking endogenous ligands, Tax1 alters normal scaffolding networks, contributing to abnormal cell proliferation through pathways like Ras–Raf–MEK–ERK. [6] [7] Structural studies show that Tax1 binds each PDZ domain in Scribble with distinct affinities and can compete with native proteins. [7] The interaction is also subject to regulation through phosphorylation, revealing a potential control point in this oncogenic mechanism. [7]
The PDZ-binding motif of Tax1 is a short amino acid sequence located at its C-terminus that fits a common class I motif, usually ending in threonine–glutamate–valine. [7] This conserved structure allows Tax1 to bind with high specificity to PDZ domains—modular protein regions involved in organizing signaling complexes. [7] Tax1's PDZ binding motif mimics cellular ligands, enabling it to fit into the grooves of multiple PDZ domains without requiring major conformational changes. [7]
Scribble is a scaffold protein that helps maintain cell polarity and limits cell growth. [7] [8] Tax1 binds all four of Scribble’s PDZ domains with differing strengths: PDZ1 (KD = 7.8 μM), PDZ2 (15.4 μM), PDZ3 (9.1 μM), and PDZ4 (40.2 μM). [7] These interactions prevent Scribble from forming complexes with its normal partners, such as β-PIX and Vangl2, leading to disrupted polarity signaling. [7] As a result, Scribble becomes mislocalized within the cell, weakening its tumor suppressor role. [7] Research also shows that phosphorylation of Tax1 at a specific threonine residue (Thr351) reduces its ability to bind PDZ domains, indicating that this interaction may be regulated by cellular signaling. [7]
Erbin is another PDZ domain-containing tumor suppressor that plays a role in localizing and regulating the Ras–Raf–MEK–ERK pathway, a major driver of cell growth. [6] [8] In cells where Erbin is present, Tax1 binding leads to increased activation of Ras and Raf proteins, enhancing downstream ERK signaling. [6] This sustained activation can drive cell division beyond normal controls and supports the growth of transformed cells. [6] [7]
Tax1 hijacks host signaling networks by using its conserved C-terminal PDZ-binding motif to bind tumor suppressor proteins like Scribble and Erbin. [6] [7] [8] These interactions disrupt pathways responsible for cell polarity and growth regulation, including the Ras–Raf–MEK–ERK signaling cascade. [6] [7] [8] By mimicking cellular ligands and targeting PDZ domains with specific binding affinities, Tax1 reprograms scaffolding proteins in a way that supports oncogenic transformation. [6] [7] [8]