Dataset Information

Torsin ATPases: Harnessing Dynamic Instability for Function.

ABSTRACT: Torsins are essential, disease-relevant AAA+ (ATPases associated with various cellular activities) proteins residing in the endoplasmic reticulum and perinuclear space, where they are implicated in a variety of cellular functions. Recently, new structural and functional details about Torsins have emerged that will have a profound influence on unraveling the precise mechanistic details of their yet-unknown mode of action in the cell. While Torsins are phylogenetically related to Clp/HSP100 proteins, they exhibit comparatively weak ATPase activities, which are tightly controlled by virtue of an active site complementation through accessory cofactors. This control mechanism is offset by a TorsinA mutation implicated in the severe movement disorder DYT1 dystonia, suggesting a critical role for the functional Torsin-cofactor interplay in vivo. Notably, TorsinA lacks aromatic pore loops that are both conserved and critical for the processive unfolding activity of Clp/HSP100 proteins. Based on these distinctive yet defining features, we discuss how the apparent dynamic nature of the Torsin-cofactor system can inform emerging models and hypotheses for Torsin complex formation and function. Specifically, we propose that the dynamic assembly and disassembly of the Torsin/cofactor system is a critical property that is required for Torsins' functional roles in nuclear trafficking and nuclear pore complex assembly or homeostasis that merit further exploration. Insights obtained from these future studies will be a valuable addition to our understanding of disease etiology of DYT1 dystonia.

SUBMITTER: Chase AR

PROVIDER: S-EPMC5425593 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Torsin ATPases: Harnessing Dynamic Instability for Function.

Chase Anna R AR Laudermilch Ethan E Schlieker Christian C

Frontiers in molecular biosciences 20170511

Torsins are essential, disease-relevant AAA+ (ATPases associated with various cellular activities) proteins residing in the endoplasmic reticulum and perinuclear space, where they are implicated in a variety of cellular functions. Recently, new structural and functional details about Torsins have emerged that will have a profound influence on unraveling the precise mechanistic details of their yet-unknown mode of action in the cell. While Torsins are phylogenetically related to Clp/HSP100 protei ...[more]

PMID: 28553638

Similar Datasets

Project description:P4-ATPases comprise a family of P-type ATPases that actively transport or flip phospholipids across cell membranes. This generates and maintains membrane lipid asymmetry, a property essential for a wide variety of cellular processes such as vesicle budding and trafficking, cell signaling, blood coagulation, apoptosis, bile and cholesterol homeostasis, and neuronal cell survival. Some P4-ATPases transport phosphatidylserine and phosphatidylethanolamine across the plasma membrane or intracellular membranes whereas other P4-ATPases are specific for phosphatidylcholine. The importance of P4-ATPases is highlighted by the finding that genetic defects in two P4-ATPases ATP8A2 and ATP8B1 are associated with severe human disorders. Recent studies have provided insight into how P4-ATPases translocate phospholipids across membranes. P4-ATPases form a phosphorylated intermediate at the aspartate of the P-type ATPase signature sequence, and dephosphorylation is activated by the lipid substrate being flipped from the exoplasmic to the cytoplasmic leaflet similar to the activation of dephosphorylation of Na(+)/K(+)-ATPase by exoplasmic K(+). How the phospholipid is translocated can be understood in terms of a peripheral hydrophobic gate pathway between transmembrane helices M1, M3, M4, and M6. This pathway, which partially overlaps with the suggested pathway for migration of Ca(2+) in the opposite direction in the Ca(2+)-ATPase, is wider than the latter, thereby accommodating the phospholipid head group. The head group is propelled along against its concentration gradient with the hydrocarbon chains projecting out into the lipid phase by movement of an isoleucine located at the position corresponding to an ion binding glutamate in the Ca(2+)- and Na(+)/K(+)-ATPases. Hence, the P4-ATPase mechanism is quite similar to the mechanism of these ion pumps, where the glutamate translocates the ions by moving like a pump rod. The accessory subunit CDC50 may be located in close association with the exoplasmic entrance of the suggested pathway, and possibly promotes the binding of the lipid substrate. This review focuses on properties of mammalian and yeast P4-ATPases for which most mechanistic insight is available. However, the structure, function and enigmas associated with mammalian and yeast P4-ATPases most likely extend to P4-ATPases of plants and other organisms.

Dataset Information

Torsin ATPases: Harnessing Dynamic Instability for Function.

Publications

Torsin ATPases: Harnessing Dynamic Instability for Function.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets