Polarity Disparity Governs Hierarchical Arrangements in Multiphase Condensates
Open Access
- Author:
- Tang, Yuqi
- Graduate Program:
- Chemistry (MS)
- Degree:
- Master of Science
- Document Type:
- Master Thesis
- Date of Defense:
- September 28, 2021
- Committee Members:
- Xin Zhang, Thesis Advisor/Co-Advisor
Tae-Hee Lee, Committee Member
Philip Bevilacqua, Program Head/Chair
Ruobo Zhou, Committee Member - Keywords:
- Phase Separation
Multilayered Condensates
Elastin-like Polypeptides
Tau protein - Abstract:
- Phase separation is a process through which a homogenous mixture of macromolecules spontaneously segregates into two distinct phases, usually a condensed phase surrounded by a dilute phase. Eukaryotic cells apply this strategy in forming membraneless organelles to dynamically regulate complex biochemical reactions. Aberrant phase transitions of these membraneless organelles are associated with disease phenotypes. Despite this long-established appreciation, how phase separation occurs to form biological condensates and how multiple sub-compartments are regulated within condensed phase remain enigmatic. Many studies have proposed sophisticated theories regarding the biophysical and molecular grammar that might regulate phase behaviors of condensates both in vitro and in cells. However, the physical and chemical principles that regulate multi-component protein condensates still remain elusive. Recent findings in our lab suggested that polarities of subcompartments play crucial roles in regulating the formation and organization of multilayered droplets through simplified polypeptide model—elastin-like polypeptides (ELPs). In particular, ELPs with low polarity difference are prone to form single phase protein condensates, whereas ELPs with high polarity difference are envisioned to form multiphase droplets, resembling “core-shell” structures, with more polar ELP is partitioned in the shell layer. The research covered in this thesis, introduced endogenous tau protein to the existing ELP system, and the structures of droplets formed between tau and V2I7E40 were successfully modified through the addition of polyU. The interaction between tau protein and polyU reduced the polarity of tau protein, causing previously miscible V2I7E40-tau droplets to segregate into layered core-shell structures. Therefore, this work provided strong evidence supporting the notion that polarity plays an important role to determine substructure of multi-component condensates. This knowledge may serve as a general principle that could be applied in explaining the organization of macromolecules within biological condensates.