N-terminal tail prolines of Gal-3 mediate its oligomerization/phase separation

Abstract

Galectins are a class of proteins that bind to β-galactose–containing glycoconjugates and play critical roles in developmental, homeostatic, and pathological contexts (1, 2). Expressed across animal tissues, galectins are synthesized in the cytoplasm and trafficked to the extracellular milieu via the unconventional secretion pathway, although they may also be localized within the cytoplasm and nuclei of cells (3). Secreted galectins bind to cell surface glycoconjugates and modulate adhesion of cells to each other and to the extracellular matrix, as well as exert influence on intracellular signaling (4, 5). All galectins possess one or two evolutionarily conserved carbohydrate recognition domains (CRDs) that are responsible for binding their cognate sugars (6). Shaped like a jelly roll, the structure of a CRD consists of two opposing β-sheets: a five-stranded F-face and a six-stranded sugar-binding S-face. Among galectins, only galectin-3 (Gal-3) belongs to the chimera type: It is characterized by a long and intrinsically disordered proline-rich N-terminal tail (NT) (7). Binding to cell surface glycoconjugates induces secreted Gal-3 to oligomerize through mechanisms that are as yet incompletely understood; quantitative precipitation studies indicate that Gal-3 may pentamerize in the presence of multivalent glycan ligands and form heterogeneous disorganized complexes with the latter (8). The multimerization of Gal-3 has been proposed to occur both by self-association through its C-terminal CRDs as well as through self-association of its NTs (9). In addition, the NT has been shown to form intramolecular links with the F-face of Gal-3 CRD (which implies a potential unification of the self-association models) (10). However, the exact role of NT in the specific cellular functions of Gal-3 is still unclear. Equally enigmatic is the presence of multiple prolines in the NT of Gal-3. In PNAS, Zhao et al. (11) address these important questions. … [↵][1]1To whom correspondence may be addressed. Email: ramray{at}iisc.ac.in. [1]: #xref-corresp-1-1