Translocon Declogger Ste24 Protects against IAPP Oligomer-Induced Proteotoxicity

Kayatekin, Can; Amasino, Audra; Gaglia, Giorgio; Flannick, Jason; Bonner, Julia Maeve; Fanning, Saranna; Narayan, Priyanka; Barrasa, M. Inmaculada; Pincus, David; Landgraf, Dirk; Nelson, J. Daniel; Hesse, William R.; Costanzo, Michael; Myers, Chad L.; Boone, Charles; Florez, José C.; Lindquist, Susan

doi:10.1016/j.cell.2018.02.026

Cited by 48 publications

(60 citation statements)

References 58 publications

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“…The ZMP Core and Accessory modules are capped by a membrane‐spanning α‐barrel module, so named because of our current lack of understanding of its functional role. In light of the ever‐growing literature of Ste24 family orthologs and emergent clinically relevant roles of HsSte24, the Tripartite Architecture will aid in the interpretation of disparate functional data. Furthermore, our proposed Tripartite Architecture can act as a platform to design experiments to better understand both the functional overlap and individual uniqueness of Ste24 family enzymes among different family orthologs (eg, fungal/mammalian/plant/protist).…”

Section: Resultsmentioning

confidence: 99%

“…Trp97 is located in the α1‐helix and rests at the center of an interfacial, hydrophobic pocket formed from residues of TM α‐helices III and VII, and Phe340 of helix α4. Although functions of absolutely conserved residues “distal” to the Ste24 active site are currently unknown, recent studies implicating HsSte24 as a “translocon unclogger” indicate the presence of functional “hot spots” far from the active site . Roles for absolutely conserved residues of the α‐barrel module in essential “nonenzymatic” functions may also exist; these could include residues essential for biogenesis or protein stability.…”

Section: Discussionmentioning

confidence: 99%

“…The cellular role for Ste24 family enzymes has expanded recently, beyond its role in prenylated protein processing. Both fungal (yeast) and human Ste24 have been shown to clear clogged translocons . Importantly, recent in vitro studies demonstrate that Ste24 can act as a generalized, integral membrane protein protease upon diverse substrates, without requiring the presence of a farnesyl moiety for substrate recognition and cleavage .…”

Section: Introductionmentioning

confidence: 99%

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The tripartite architecture of the eukaryotic integral membrane protein zinc metalloprotease Ste24

2019

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Ste24 enzymes, a family of eukaryotic integral membrane proteins, are zinc metalloproteases (ZMPs) originally characterized as “CAAX proteases” targeting prenylated substrates, including a‐factor mating pheromone in yeast and prelamin A in humans. Recently, Ste24 was shown to also cleave nonprenylated substrates. Reduced activity of the human ortholog, HsSte24, is linked to multiple disease states (laminopathies), including progerias and lipid disorders. Ste24 possesses a unique “α‐barrel” structure consisting of seven transmembrane (TM) α‐helices encircling a large intramembranous cavity (~14 000 Å3). The catalytic zinc, coordinated via a HExxH…E/H motif characteristic of gluzincin ZMPs, is positioned at one of the cavity's bases. The interrelationship between Ste24 as a gluzincin, a long‐studied class of soluble ZMPs, and as a novel cavity‐containing integral membrane protein protease has been minimally explored to date. Informed by homology to well‐characterized soluble, gluzincin ZMPs, we develop a model of Ste24 that provides a conceptual framework for this enzyme family, suitable for development and interpretation of structure/function studies. The model consists of an interfacial, zinc‐containing “ZMP Core” module surrounded by a “ZMP Accessory” module, both capped by a TM helical “α‐barrel” module of as yet unknown function. Multiple sequence alignment of 58 Ste24 orthologs revealed 38 absolutely conserved residues, apportioned unequally among the ZMP Core (18), ZMP Accessory (13), and α‐barrel (7) modules. This Tripartite Architecture representation of Ste24 provides a unified image of this enzyme family.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The tripartite architecture of the eukaryotic integral membrane protein zinc metalloprotease Ste24

2019

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“…We thus constructed a structural model of HtpX using the robetta program (Fig. ), based on the crystal structure of the CAAX protease, ZMPSTE24 , a human homolog of HtpX that is also involved in protein quality control in ER in addition to the CAAX cleavage, and mapped the mutation sites . The core domain that contains the protease active site of this model shares several structural features, such as relative arrangement of secondary structures and the predicted active site residues, with those of the other M48 proteases .…”

Section: Discussionmentioning

confidence: 99%

An in vivo protease activity assay for investigating the functions of the Escherichia coli membrane protease HtpX

2019

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Escherichia coli HtpX is an M48 family zinc metalloproteinase located in the cytoplasmic membrane. Previous studies suggested that it is involved in the quality control of membrane proteins. However, its in vivo proteolytic function has not been characterized in detail, mainly because the physiological substrates have not been identified and no model substrate that allows sensitive detection of the protease activity is available. We constructed a new model substrate of HtpX and established an in vivo semiquantitative and convenient protease activity assay system for HtpX. This system enables detection of differential protease activities of HtpX mutants carrying mutations in conserved regions. This system would also be useful for investigating the functions of HtpX and its homologs in other bacteria.

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“…This first report of Ste24 as translocon unclogger utilized a "clogging" chimera comprising bacterial and yeast protein domains. A 2018 publication, from a different research group, identified Ste24 as having a similar function against human islet amyloid polypeptide [45], which commonly misfolds in patients with type 2 diabetes (with this "oligomer-induced proteotoxicity" inducing βcell failure). These results, collectively, suggest a role for Ste24 in the ER-associated degradation pathway [46].…”

Section: Translocon Unclogging and Diabetesmentioning

confidence: 99%

Ste24: An Integral Membrane Protein Zinc Metalloprotease with Provocative Structure and Emergent Biology

Goblirsch

Wiener

2020

Journal of Molecular Biology

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Ste24, an integral membrane protein zinc metalloprotease, is found in every kingdom of eukaryotes. It was discovered approximately 20 years ago by yeast genetic screens identifying it as a factor responsible for processing the yeast mating a-factor pheromone. In animals, Ste24 processes prelamin A, a component of the nuclear lamina; mutations in the human ortholog of Ste24 diminish its activity, giving rise to genetic diseases of accelerated aging (progerias). Additionally, lipodystrophy, acquired from the standard highly active antiretroviral therapy used to treat AIDS patients, likely results from off-target interactions of HIV (aspartyl) protease inhibitor drugs with Ste24. Ste24 possesses a novel "α-barrel" structure, consisting of a ring of seven transmembrane α-helices enclosing a large (N 12,000 Å 3 ) interior volume that contains the active-site and substrate-binding region; this "membrane-interior reaction chamber" is unprecedented in integral membrane protein structures. Additionally, the surface of the membrane-interior reaction chamber possesses a strikingly large negative electrostatic surface potential, adding additional "functional mystery." Recent publications implicate Ste24 as a key factor in several endoplasmic reticulum processes, including the unfolded protein response, a cellular stress response of the endoplasmic reticulum, and removal of misfolded proteins from the translocon. Ste24, with its provocative structure, enigmatic mechanism, and recently emergent new biological roles including "translocon unclogger" and (non-enyzmatic) broad-spectrum viral restriction factor, presents far differently than before 2016, when it was viewed as a "CAAX protease" responsible for cleavage of prenylated (farnesylated or geranylgeranylated) substrates. The emphasis of this review is on Ste24 of the "Post-CAAX-Protease Era."

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Translocon Declogger Ste24 Protects against IAPP Oligomer-Induced Proteotoxicity

Cited by 48 publications

References 58 publications

The tripartite architecture of the eukaryotic integral membrane protein zinc metalloprotease Ste24

The tripartite architecture of the eukaryotic integral membrane protein zinc metalloprotease Ste24

An in vivo protease activity assay for investigating the functions of the Escherichia coli membrane protease HtpX

Ste24: An Integral Membrane Protein Zinc Metalloprotease with Provocative Structure and Emergent Biology

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