Biology subjects

Nayak, V.

Publications and source records attributed to Nayak, V..

4 recordsLinked to original sources

bioRxiv2026

P-Rex2 exhibits unique structural features and regulatory mechanisms distinct from the closely related RhoGEF P-Rex1

Rho guanine-nucleotide exchange factors (RhoGEFs) activate small GTPases to drive cytoskeletal rearrangement, cell motility, and proliferation. The phosphatidylinositol-3,4,5-trisphosphate (PIP3)-dependent Rac exchanger (P-Rex) subfamily of RhoGEFs includes P-Rex1 and P-Rex2 which, when misregulated, contribute to cancer progression and metastasis. P-Rex activity is controlled by accessory domains that maintain the protein in a cytosolic, autoinhibited state until activated by the lipid PIP3 and G protein {beta}{gamma} subunits. While P-Rex1 autoinhibition has been structurally and biochemically characterized, P-Rex2 has remained largely unexplored. Furthermore, despite high sequence similarity and domain conservation, P-Rex homologs differ in substrate specificity and regulatory interactions, and the molecular basis for these divergences is unknown. Here, we have taken an integrative structural biology approach to investigate these gaps. Using cryo-EM, we determined the first structure of full-length P-Rex2 to moderate resolution, revealing that, while the overall structure closely resembles that of P-Rex1, there is a substantial repositioning of the N-terminal module relative to the C-terminal core. This may play a key role in precluding the intramolecular interactions between the N- and C-terminal domains that are observed in autoinhibited P-Rex1. Hydrogen-deuterium exchange mass spectrometry revealed that, unlike P-Rex1, P-Rex2 dynamics are unaffected by IP4, the headgroup of PIP3. SEC-SAXS data support that the N-terminal module itself is less dynamic, and biochemical assays show that P-Rex2 may be more tightly regulated by autoinhibition, likely through a mechanism different from P-Rex1. These findings uncover unique features in the molecular mechanisms of P-Rex2 regulation.

biochemistry↗

bioRxiv2025

Pace of life predicts parasite resistance and fecundity tolerance, but not mortality tolerance, among Trinidadian guppies, Poecilia reticulata

Host defence against parasites can include limiting parasite growth, resistance, limiting the mortality cost of infection, mortality tolerance, and limiting the reproductive cost of infection, fecundity tolerance. Theoretically, these three host strategies have very different epidemiological and evolutionary outcomes. In particular, because mortality tolerance increases parasite population size, it is under strong positive frequency-dependent selection and may therefore be less variable between populations than either resistance or fecundity tolerance. Additionally, host investment in each strategy can be expected to differ between populations that experience different ecological conditions. Here, we tested how populations of Trinidadian guppies Poecilia reticulata from the upper and lower courses of three rivers responded to experimental infection with a novel strain of Gyrodactylus turnbulli. In line with theoretical predictions, we found that lower course populations, previously shown to have faster paces of life, invested less in resistance and fecundity tolerance - but not mortality tolerance - than the upper course populations with slower paces of life. Our results indicate that this host-parasite interaction both conforms to evolutionary-epidemiological theoretical predictions, and is shaped by broader ecological conditions.

evolutionary biology↗

bioRxiv2024

Select autosomal dominant DFNA11 deafness mutations activate Myo7A in epithelial cells

Myosin-7A (Myo7A) is a motor protein crucial for the organization and function of stereocilia, specialized actin-rich protrusions on the surface of inner ear hair cells that mediate hearing. Mutations in Myo7A cause several forms of genetic hearing loss, including autosomal dominant DFNA11 deafness. Despite its importance, the structural elements of Myo7A that control its motor activity within cells are not well understood. In this study, we used cultured kidney epithelial cells to screen for mutations that activate the motor-dependent targeting of Myo7A to the tips of apical microvilli on these cells. Our findings reveal that Myo7A is regulated by specific IQ motifs within its lever arm, and that this regulation can function at least partially independent of its tail sequence. Importantly, we demonstrate that many of the DFNA11 deafness mutations reported in patients activate Myo7A targeting, providing a potential explanation for the autosomal dominant genetics of this form of deafness.

cell biology↗

bioRxiv2023

Biochemical characterization of a GDP-mannose transporter from Chaetomium thermophilum

Nucleotide Sugar Transporters (NSTs) belong to the SLC35 family (human solute carrier) of membrane transport proteins and are crucial components of the glycosylation machinery. NSTs are localized in the ER and Golgi apparatus membranes, where they accumulate nucleotide sugars from the cytosol for subsequent polysaccharide biosynthesis. Loss of NST function impacts the glycosylation of cell surface molecules. Mutations in NSTs cause several developmental disorders, immune disorders, and increased susceptibility to infection. Atomic resolution structures of three NSTs have provided a blueprint for a detailed molecular interpretation of their biochemical properties. In this work, we have identified, cloned, and expressed 18 members of the SLC35 family from various eukaryotic organisms in Saccharomyces cerevisiae. Out of 18 clones, we determined Vrg4 from Chaetomium thermophilum (CtVrg4) is a GDP-mannose transporter with an enhanced melting point temperature (Tm) of 56.9 {degrees}C, which increases with the addition of substrates, GMP and GDP-mannose. In addition, we report--for the first time--that the CtVrg4 shows an affinity to bind to phosphatidylinositol lipids.

biochemistry↗