scholarly journals AAA+ ATPases: structural insertions under the magnifying glass

2021 ◽  
Vol 66 ◽  
pp. 119-128
Author(s):  
Matthew Jessop ◽  
Jan Felix ◽  
Irina Gutsche
Keyword(s):  
Aaa Atpases

scholarly journals Breakdown of Filamentous Myofibrils by the UPS–Step by Step

Biomolecules ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 110
Author(s):  
Dina Aweida ◽  
Shenhav Cohen
Keyword(s):  
Protein Quality ◽  
Protein Structures ◽  
Ubiquitin Proteasome System ◽  
Surface Proteins ◽  
Catalytic Core ◽  
Complex Protein ◽  
Ubiquitin Proteasome ◽  
Aaa Atpases

Protein degradation maintains cellular integrity by regulating virtually all biological processes, whereas impaired proteolysis perturbs protein quality control, and often leads to human disease. Two major proteolytic systems are responsible for protein breakdown in all cells: autophagy, which facilitates the loss of organelles, protein aggregates, and cell surface proteins; and the ubiquitin-proteasome system (UPS), which promotes degradation of mainly soluble proteins. Recent findings indicate that more complex protein structures, such as filamentous assemblies, which are not accessible to the catalytic core of the proteasome in vitro, can be efficiently degraded by this proteolytic machinery in systemic catabolic states in vivo. Mechanisms that loosen the filamentous structure seem to be activated first, hence increasing the accessibility of protein constituents to the UPS. In this review, we will discuss the mechanisms underlying the disassembly and loss of the intricate insoluble filamentous myofibrils, which are responsible for muscle contraction, and whose degradation by the UPS causes weakness and disability in aging and disease. Several lines of evidence indicate that myofibril breakdown occurs in a strictly ordered and controlled manner, and the function of AAA-ATPases is crucial for their disassembly and loss.

scholarly journals The AAA+ ATPase p97, a cellular multitool

2017 ◽  
Vol 474 (17) ◽  
pp. 2953-2976 ◽  
Author(s):  
Lasse Stach ◽  
Paul S. Freemont
Keyword(s):  
Atp Hydrolysis ◽  
Current Status ◽  
Cellular Functions ◽  
Aaa Atpase ◽  
Cellular Processes ◽  
Proteotoxic Stress ◽  
Binding Domains ◽  
Wide Range ◽  
Aaa Atpases ◽  
Substrate Proteins

The AAA+ (ATPases associated with diverse cellular activities) ATPase p97 is essential to a wide range of cellular functions, including endoplasmic reticulum-associated degradation, membrane fusion, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation and chromatin-associated processes, which are regulated by ubiquitination. p97 acts downstream from ubiquitin signaling events and utilizes the energy from ATP hydrolysis to extract its substrate proteins from cellular structures or multiprotein complexes. A multitude of p97 cofactors have evolved which are essential to p97 function. Ubiquitin-interacting domains and p97-binding domains combine to form bi-functional cofactors, whose complexes with p97 enable the enzyme to interact with a wide range of ubiquitinated substrates. A set of mutations in p97 have been shown to cause the multisystem proteinopathy inclusion body myopathy associated with Paget's disease of bone and frontotemporal dementia. In addition, p97 inhibition has been identified as a promising approach to provoke proteotoxic stress in tumors. In this review, we will describe the cellular processes governed by p97, how the cofactors interact with both p97 and its ubiquitinated substrates, p97 enzymology and the current status in developing p97 inhibitors for cancer therapy.

scholarly journals Structural Basis for Dodecameric Assembly States and Conformational Plasticity of the Full-Length AAA+ ATPases Rvb1·Rvb2

Structure ◽  
2015 ◽  
Vol 23 (3) ◽  
pp. 483-495 ◽  
Author(s):  
Kristina Lakomek ◽  
Gabriele Stoehr ◽  
Alessandro Tosi ◽  
Monika Schmailzl ◽  
Karl-Peter Hopfner
Keyword(s):  
Full Length ◽  
Structural Basis ◽  
Conformational Plasticity ◽  
Aaa Atpases

Novel structural and functional insights into the MoxR family of AAA+ ATPases

2012 ◽  
Vol 179 (2) ◽  
pp. 211-221 ◽  
Author(s):  
Keith S. Wong ◽  
Walid A. Houry
Keyword(s):  
Aaa Atpases

scholarly journals The Emergence of the Conserved AAA+ ATPases Pontin and Reptin on the Signaling Landscape

2013 ◽  
Vol 6 (266) ◽  
pp. mr1-mr1 ◽  
Author(s):  
J. Rosenbaum ◽  
S. H. Baek ◽  
A. Dutta ◽  
W. A. Houry ◽  
O. Huber ◽  
...  
Keyword(s):  
Aaa Atpases

scholarly journals Proteasomes: unfoldase-assisted protein degradation machines

2019 ◽  
Vol 401 (1) ◽  
pp. 183-199 ◽  
Author(s):  
Parijat Majumder ◽  
Wolfgang Baumeister
Keyword(s):  
Stress Response ◽  
Molecular Machines ◽  
Molecular Architecture ◽  
Core Particle ◽  
Protein Substrates ◽  
Macromolecular Assemblies ◽  
Current State ◽  
Intracellular Proteins ◽  
Domains Of Life ◽  
Aaa Atpases

Abstract Proteasomes are the principal molecular machines for the regulated degradation of intracellular proteins. These self-compartmentalized macromolecular assemblies selectively degrade misfolded, mistranslated, damaged or otherwise unwanted proteins, and play a pivotal role in the maintenance of cellular proteostasis, in stress response, and numerous other processes of vital importance. Whereas the molecular architecture of the proteasome core particle (CP) is universally conserved, the unfoldase modules vary in overall structure, subunit complexity, and regulatory principles. Proteasomal unfoldases are AAA+ ATPases (ATPases associated with a variety of cellular activities) that unfold protein substrates, and translocate them into the CP for degradation. In this review, we summarize the current state of knowledge about proteasome – unfoldase systems in bacteria, archaea, and eukaryotes, the three domains of life.

scholarly journals Sorafenib as an Inhibitor of RUVBL2

Biomolecules ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 605 ◽  
Author(s):  
Nardin Nano ◽  
Francisca Ugwu ◽  
Thiago V. Seraphim ◽  
Tangzhi Li ◽  
Gina Azer ◽  
...  
Keyword(s):  
Atpase Activity ◽  
Competitive Inhibitor ◽  
Telomerase Activity ◽  
Size Exclusion ◽  
Scattering Data ◽  
Cellular Processes ◽  
Dna Damage Signaling ◽  
X Ray Scattering ◽  
Exclusion Chromatography ◽  
Aaa Atpases

RUVBL1 and RUVBL2 are highly conserved ATPases that belong to the AAA+ (ATPases Associated with various cellular Activities) superfamily and are involved in various complexes and cellular processes, several of which are closely linked to oncogenesis. The proteins were implicated in DNA damage signaling and repair, chromatin remodeling, telomerase activity, and in modulating the transcriptional activities of proto-oncogenes such as c-Myc and β-catenin. Moreover, both proteins were found to be overexpressed in several different types of cancers such as breast, lung, kidney, bladder, and leukemia. Given their various roles and strong involvement in carcinogenesis, the RUVBL proteins are considered to be novel targets for the discovery and development of therapeutic cancer drugs. Here, we describe the identification of sorafenib as a novel inhibitor of the ATPase activity of human RUVBL2. Enzyme kinetics and surface plasmon resonance experiments revealed that sorafenib is a weak, mixed non-competitive inhibitor of the protein’s ATPase activity. Size exclusion chromatography and small angle X-ray scattering data indicated that the interaction of sorafenib with RUVBL2 does not cause a significant effect on the solution conformation of the protein; however, the data suggested that the effect of sorafenib on RUVBL2 activity is mediated by the insertion domain in the protein. Sorafenib also inhibited the ATPase activity of the RUVBL1/2 complex. Hence, we propose that sorafenib could be further optimized to be a potent inhibitor of the RUVBL proteins.

scholarly journals Structure and mechanism of the ESCRT pathway AAA+ ATPase Vps4

2019 ◽  
Vol 47 (1) ◽  
pp. 37-45 ◽  
Author(s):  
Han Han ◽  
Christopher P. Hill
Keyword(s):  
Cell Biology ◽  
Cellular Membrane ◽  
Structural Features ◽  
Transport Pathways ◽  
Endosomal Sorting ◽  
Aaa Atpase ◽  
Protein Substrates ◽  
Membrane Fission ◽  
Aaa Atpases ◽  
Equivalent Mechanism

Abstract The progression of ESCRT (Endosomal Sorting Complexes Required for Transport) pathways, which mediate numerous cellular membrane fission events, is driven by the enzyme Vps4. Understanding of Vps4 mechanism is, therefore, of fundamental importance in its own right and, moreover, it is highly relevant to the understanding of many related AAA+ ATPases that function in multiple facets of cell biology. Vps4 unfolds its ESCRT-III protein substrates by translocating them through its central hexameric pore, thereby driving membrane fission and recycling of ESCRT-III subunits. This mini-review focuses on recent advances in Vps4 structure and mechanism, including ideas about how Vps4 translocates and unfolds ESCRT-III subunits. Related AAA+ ATPases that share structural features with Vps4 and likely utilize an equivalent mechanism are also discussed.

scholarly journals Cilia-associated cellular function of the AAA ATPases RUVBL1 and RUVBL2

2015 ◽  
Vol 2 (Suppl 1) ◽  
pp. A29
Author(s):  
Claudia Dafinger ◽  
Markus Rinschen ◽  
Carolin Ehrenberg ◽  
Mareike Franke ◽  
Heike Göbel ◽  
...  
Keyword(s):  
Cellular Function ◽  
Aaa Atpases

AAA+ ATPases Reptin and Pontin as potential diagnostic and prognostic biomarkers in salivary gland cancer - a short report

2018 ◽  
Vol 41 (4) ◽  
pp. 455-462 ◽  
Author(s):  
Jan-Henrik Mikesch ◽  
Wolfgang Hartmann ◽  
Linus Angenendt ◽  
Otmar Huber ◽  
Christoph Schliemann ◽  
...  
Keyword(s):  
Salivary Gland ◽  
Prognostic Biomarkers ◽  
Salivary Gland Cancer ◽  
Short Report ◽  
Aaa Atpases
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