Phosphoramidon inhibits the integral membrane protein zinc metalloprotease ZMPSTE24

Goblirsch, B.R.; Arachea, Buenafe T.; Councell, Daniel J.; Wiener, Michael C.

doi:10.1107/s2059798318003431

Cited by 4 publications

(18 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For the purposes of this study, we refer to this grouping as the “ZMP Core” module (Figure A). The designation of a “ZMP Core” module, shared by Ste24 with soluble ZMPs, is further supported by our recent structure of HsSte24 complexed with the classical ZMP inhibitor phosphoramidon (Figure B) . Phosphoramidon is a competitive inhibitor and transition‐state analog of several soluble ZMPs, particularly the gluzincins thermolysin (M4) and neprilysin (M13) .…”

Section: Resultsmentioning

confidence: 66%

“…Phosphoramidon is a competitive inhibitor and transition‐state analog of several soluble ZMPs, particularly the gluzincins thermolysin (M4) and neprilysin (M13) . Phosphoramidon also inhibits HsSte24 proteolysis and its binding mode, localized solely within the “ZMP Core” module, is highly conserved among these three families (M4, M13, and M48) of ZMPs …”

Section: Resultsmentioning

confidence: 99%

“…Therefore, a structure‐based search of the PDB database using the DALI server was used to identify those gluzincin families most homologous to Ste24. Currently available structures of Ste24 comprise fungal (SmSte24) and human (HsSte24) orthologs. While SmSte24 and HsSte24 structures are highly similar, Ste24 mammalian orthologs contain a variable length insert between the α3‐helix of the L5D and TM α‐helix VI (37 residues in HsSte24) (Figure S1); this insert is disordered in all HsSte24 crystal structures.…”

Section: Resultsmentioning

confidence: 99%

“…Catalytic and substrate specificity regions are indicated by C and S1′ , respectively; SmSte24 residues which are absolutely conserved in Ste24 and within these regions are explicitly labeled and bracketed. B, Superposition of the unbound SmSte24 structure with our recently determined structure of HsSte24 complexed with the ZMP inhibitor phosphoramidon (PDB 6BH8) . For clarity, only the phosphoramidon molecule (shown as green sticks) of the HsSte24:phosphoramidon structure is displayed.…”

Section: Resultsmentioning

confidence: 99%

“…Additionally, functional complementation between human and yeast Ste24 orthologs has been established in vivo where HsSte24 rescues defects in a ‐factor biogenesis associated with Ste24p knockout yeast ( ste24 Δ) . Crystal structures of yeast ( Saccharomyces mikatae ; SmSte24) and human Ste24 (HsSte24) reveal these two Ste24 structures to be highly similar (RMSD of C α atoms ~1.7 Å) . The structure of Ste24, as exemplified by SmSte24 (PDB: 4IL3), possesses a striking seven‐transmembrane (TM) helical “α‐barrel” structure encapsulating a voluminous reaction cavity (~14 000 Å 3 ; Figure A).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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

2019

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 66%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

2019

Self Cite

View full text Add to dashboard Cite

show abstract

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

Goblirsch

Wiener

2020

Journal of Molecular Biology

Self Cite

View full text Add to dashboard Cite

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."

show abstract

Built to bind: biosynthetic strategies for the formation of small-molecule protease inhibitors

Kaysser

2019

Nat. Prod. Rep.

View full text Add to dashboard Cite

show abstract

Phosphoramidon inhibits the integral membrane protein zinc metalloprotease ZMPSTE24

Cited by 4 publications

References 46 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

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

Built to bind: biosynthetic strategies for the formation of small-molecule protease inhibitors

Contact Info

Product

Resources

About