Galectin-3 N-terminal tail prolines modulate cell activity and glycan-mediated oligomerization/phase separation
| Autor: | Avraham Raz, Michelle C. Miller, Hongming Gu, Hairong Cheng, Kevin H. Mayo, Zihan Zhao, Guihua Tai, Zhen He, Zhongyu Zhang, Yifa Zhou, Xuejiao Xu |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Glycan
Glycosylation Proline Galectin 3 Galectins Cell Carbohydrates medicine.disease_cause Endocytosis 03 medical and health sciences 0302 clinical medicine Cell surface receptor Polysaccharides medicine Humans 030304 developmental biology chemistry.chemical_classification 0303 health sciences Mutation Multidisciplinary Binding Sites biology Cell migration Blood Proteins Biological Sciences Cell biology medicine.anatomical_structure chemistry biology.protein Glycoprotein 030217 neurology & neurosurgery Function (biology) Protein Binding |
| Zdroj: | Proc Natl Acad Sci U S A |
| ISSN: | 1091-6490 |
| Popis: | Galectin-3 (Gal-3) has a long, aperiodic, and dynamic proline-rich N-terminal tail (NT). The functional role of the NT with its numerous prolines has remained enigmatic since its discovery. To provide some resolution to this puzzle, we individually mutated all 14 NT prolines over the first 68 residues and assessed their effects on various Gal-3–mediated functions. Our findings show that mutation of any single proline (especially P37A, P55A, P60A, P64A/H, and P67A) dramatically and differentially inhibits Gal-3–mediated cellular activities (i.e., cell migration, activation, endocytosis, and hemagglutination). For mechanistic insight, we investigated the role of prolines in mediating Gal-3 oligomerization, a fundamental process required for these cell activities. We showed that Gal-3 oligomerization triggered by binding to glycoproteins is a dynamic process analogous to liquid–liquid phase separation (LLPS). The composition of these heterooligomers is dependent on the concentration of Gal-3 as well as on the concentration and type of glycoprotein. LLPS-like Gal-3 oligomerization/condensation was also observed on the plasma membrane and disrupted endomembranes. Molecular- and cell-based assays indicate that glycan binding–triggered Gal-3 LLPS (or LLPS-like) is driven mainly by dynamic intermolecular interactions between the Gal-3 NT and the carbohydrate recognition domain (CRD) F-face, although NT–NT interactions appear to contribute to a lesser extent. Mutation of each proline within the NT differentially controls NT–CRD interactions, consequently affecting glycan binding, LLPS, and cellular activities. Our results unveil the role of proline polymorphisms (e.g., at P64) associated with many diseases and suggest that the function of glycosylated cell surface receptors is dynamically regulated by Gal-3. |
| Databáze: | OpenAIRE |
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