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Gingras, R. M.

Publications and source records attributed to Gingras, R. M..

3 recordsLinked to original sources

Generation and characterization of conditional yeast mutants affecting each of the two essential functions of the scaffolding proteins Boi1/2 and Bem1

Boi1 and Boi2 are closely related yeast scaffolding proteins, either of which can perform an essential function. Previous studies have suggested a role in cell polarity, interacting with lipids, components of the late secretory pathway, and actin nucleators. We report detailed studies of their localization, dynamics, and the generation and characterization of conditional mutants. Boi1/2 are present on the plasma membrane in dynamic patches, then at the bud neck during cytokinesis. These distributions are unaffected by perturbation of the actin cytoskeleton or the secretory pathway. We identify two critical aromatic residues, present in both Boi1 and Boi2, in the essential C-terminal PH domain, that cause temperature sensitive growth resulting in defects in polarized growth leading to cell lysis. The scaffolding protein, Bem1, colocalizes with Boi1 in patches at the growing bud, and at the bud neck, the latter requiring the N-terminal SH3 domain of Boi1p. Loss of function of Boi1-SH3 domain renders Bem1 essential which can be fully replaced by a fusion of the SH3b and PB1 domains of Bem1. Thus, the two essential functions of the Boi1/2/Bem1 proteins can be satisfied by Bem1-SH3b-PB1 and Boi1-PH. Generation and characterization of conditional mutations in the essential function of Bem1 reveal a slow onset of defects in polarized growth, which is difficult to define a specific initial defect. This study provides more details into the functions of Boi1/2 and their relationship with Bem1, and presents the generation of conditional mutants that will be useful for future genetic analysis.

cell biology↗

High-resolution secretory timeline from vesicle formation at the Golgi to fusion at the plasma membrane in S. cerevisiae

Most of the components in the yeast secretory pathway have been studied, yet a high resolution temporal timeline of their participation is lacking. Here we define the order of acquisition, lifetime, and release of critical components involved in late secretion from the Golgi to the plasma membrane. Of particular interest is the timing of the many reported effectors of the secretory vesicle Rab protein Sec4, including the myosin-V Myo2, the exocyst complex, the lgl homolog Sro7, and the small yeast-specific protein Mso1. At the trans-Golgi network (TGN) Sec4s GEF, Sec2, is recruited to Ypt31-positive compartments, quickly followed by Sec4 and Myo2 and vesicle formation. While transported to the bud tip, the entire exocyst complex, including Sec3, is assembled on to the vesicle. Before fusion, vesicles tether for 5s, during which the vesicle retains the exocyst complex and stimulates lateral recruitment of Rho3 on the plasma membrane. Sec2 and Myo2 are rapidly lost, followed by recruitment of cytosolic Sro7, and finally the SM protein Sec1, which appears for just 2 seconds prior to fusion. Perturbation experiments reveal an ordered and robust series of events during tethering that provide insights into the function of Sec4 and effector exchange.

cell biology↗

Yeast Rgd3 is a phospho-regulated F-BAR-containing RhoGAP involved in the regulation of Rho3 distribution and cell morphology

Polarized growth requires the integration of polarity pathways with the delivery of exocytic vesicles for cell expansion and counterbalancing endocytic uptake. In budding yeast, the myosin-V Myo2 is aided by the kinesin-related protein Smy1 in carrying out the essential Sec4-dependent transport of secretory vesicles to sites of polarized growth. Over-expression suppressors of a conditional myo2 smy1 mutant identified a novel F-BAR-containing RhoGAP, Rgd3, that has activity primarily on Rho3, but also Cdc42. Internally tagged Rho3 is restricted to the plasma membrane in a gradient corresponding to cell polarity that is altered upon Rgd3 over-expression. Rgd3 itself is localized to dynamic polarized vesicles that, while distinct from constitutive secretory vesicles, are dependent on actin and Myo2 function. In vitro Rgd3 associates with liposomes in a PIP2-enhanced manner. Further, the Rgd3 C-terminal region contains several phosphorylatable residues within a reported SH3-binding motif. An unphosphorylated mimetic construct is active and highly polarized, while the phospho-mimetic form is not. Rgd3 is capable of activating Myo2, dependent on its phospho-state and Rgd3 overexpression rescues aberrant Rho3 localization and cell morphologies seen at the restrictive temperature in the myo2 smy1 mutant. We propose a model where Rgd3 functions to modulate and maintain Rho3 polarity during growth.

cell biology↗