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The CAAX prenyl protease CAAX PP.  The 3-d structure (2.0 Å resolution) revealed a seven TMS α-helical barrel structure surrounding a large water-filled intramembrane chanber capped by a zinc metalloprotease domain with the catlytic site facing into the chamber.  Mutations cause laminopathies (Quigley et al. 2013). results showed: (1) a detailed view of the active site of ZMPSTE24, including water coordinating the catalytic zinc; (2) enhanced visualization of fenestrations providing access from the exterior to the interior cavity of the protein; (3) a view of the C-terminus extending away from the main body of the protein; (4) localization of ordered lipid and detergent molecules at internal and external surfaces and also projecting through fenestrations, and (5) water molecules associated with the surface of the internal cavity (Clark et al. 2017). A tripartite architecture of the human zinc metalloprotease Ste24 has been proposed (Goblirsch et al. 2019; see family description).


CAAX PP of Homo sapiens (O75844)

The CAAX prenyl protease CAAX PP

CAAX PP of Arabidopsis thaliana (Q8RX88)

The CAAX integral membrane zinc prenyl metaloprotease, CAAX PP or Ste24p of 453 aas and 7 TMSs, found in every kingdom of eukaryotes. It's 3-D structure has been solved (Goblirsch and Wiener 2020). It is a factor responsible for processing the yeast mating a-factor pheromone. In animals, Ste24 processes prelamin, 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 (HAART) 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 (> 12,000 Å3) 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. Ste24p may be a key factor in several endoplasmic reticulum (ER) processes, including the unfolded protein response, a cellular stress response of the ER, and removal of misfolded proteins from the translocon. Ste24p is thus a "translocon unclogger". Goblirsch and Wiener 2020

have reviewed the sturcture and functions of Ste24 structure.

CAAX PP of Sacharomyces cerevisiae (P47154)

Ste24 endopeptidase, CAAX PP of 407 aas and 7 TMSs.  The crystal structure has been solved showing that the Ste24p core structure is a ring of seven TMSs enclosing a voluminous cavity containing the active site and substrate-binding groove. The cavity is large enough to hold hundreds of water molecules, and is accessible to the external milieu by means of gaps between splayed transmembrane helices (Sanders and Hutchison 2018). Possibly cleavage proceeds by means of a processive mechanism of substrate insertion, translocation, and ejection (Pryor et al. 2013). The active site is just under the interfacial lid of the barrel, with substrate entry and product exit through fenestrations located near the upper end of the barrel, just under the water-bilayer interface (Sanders and Hutchison 2018).

endopeptidase of Helicobacter pylori (J0MMU8)

Protease HtpX homologue of 295 aas

HtpX homologue of Leptospira interrogans

Membrane-localized protease able to endoproteolytically degrade overproduced SecY and other membrane protein. Probably plays a role in the quality control of integral membrane proteins (Arolas et al. 2014).

HtpX of E. coli

Peptidase M48 of 300 aas

Candidatus Saccharibacteria
Peptidase M48 Ste24p of Candidatus Saccharibacteria bacterium

Protease HtpX of 841 aas and 11 TMSs with an HtpX domain.

Candidatus Lokiarchaeota
HtpX of Lokiarchaeum sp. GC14_75

M48 family metalloprotease of 405 aas and 4 TMSs in a 2 + 2 TMS arrangement.

Protease of Lachnoclostridium sp. An298

CAAX prenyl protease 2, RCE1 (Ashby, 1998). A member of the Abi Superfamily.

RCE1 of Saccharomyces cerevisiae (Q03530)

CAAX prenyl protease 2 of 304 aas

CAAX protease of Fusarum oxysporum

CAAX prenyl protease 2 of 277 aas

CAAX protease of Paramecium tetraurelia

CAAX prenyl protease 2

CAAX protease 2 of Trypanosoma cruzi

CAAX prenyl protease 2 of 311 aas

CAAX protease 2 of Arabidopsis thaliana

CAAX prenyl protease 2 of 237 aas

CAAX protease 2 of Entamoeba histolytica