8.A.142. The PAT Intramembrane Chaperone Complex (PAT) Family In eukaryotes, the majority of membrane proteins are inserted, modified and folded in the endoplasmic reticulum (ER). Very little is known about how multi-spanning membrane proteins with several TMSs are assembled within the membrane. During the assembly of TMSs, interactions between polar or charged amino acids typically stabilize the final folded configuration. TMSs with hydrophilic amino acyl residues are chaperoned during the co-translational biogenesis. Chitwood and Hegde 2020 identified the PAT complex, an abundant obligate heterodimer of the widely conserved ER-resident membrane proteins CCDC47 and Asterix. The PAT complex engages nascent TMSs that contain unshielded hydrophilic side chains within the lipid bilayer, and it disengages concomitant with substrate folding. Cells that lack either subunit of the PAT complex show reduced biogenesis of numerous multi-spanning membrane proteins. Thus, the PAT complex is an intramembrane chaperone that protects TMSs during assembly to minimize misfolding of multi-spanning membrane proteins and maintain cellular protein homeostasis. The regulatory network and targeted interventions for CCDC family members in tumor pathogenesis have been reviewed (Liu et al. 2023).
References:
Chitwood, P.J. and R.S. Hegde. (2020). An intramembrane chaperone complex facilitates membrane protein biogenesis. Nature 584: 630-634.
Liu, Z., W. Yan, S. Liu, Z. Liu, P. Xu, and W. Fang. (2023). Regulatory network and targeted interventions for CCDC family in tumor pathogenesis. Cancer Lett 565: 216225. [Epub: Ahead of Print]
Morimoto, M., H. Waller-Evans, Z. Ammous, X. Song, K.A. Strauss, D. Pehlivan, C. Gonzaga-Jauregui, E.G. Puffenberger, C.R. Holst, E. Karaca, K.W. Brigatti, E. Maguire, Z.H. Coban-Akdemir, A. Amagata, C.C. Lau, X. Chepa-Lotrea, E. Macnamara, T. Tos, S. Isikay, M. Nehrebecky, J.D. Overton, M. Klein, T.C. Markello, J.E. Posey, D.R. Adams, E. Lloyd-Evans, J.R. Lupski, W.A. Gahl, and M.C.V. Malicdan. (2018). Bi-allelic CCDC47 Variants Cause a Disorder Characterized by Woolly Hair, Liver Dysfunction, Dysmorphic Features, and Global Developmental Delay. Am J Hum Genet 103: 794-807.
Smalinskaitė, L., M.K. Kim, A.J.O. Lewis, R.J. Keenan, and R.S. Hegde. (2022). Mechanism of an intramembrane chaperone for multipass membrane proteins. Nature. [Epub: Ahead of Print]
Yamamoto, S., T. Yamazaki, S. Komazaki, T. Yamashita, M. Osaki, M. Matsubayashi, H. Kidoya, N. Takakura, D. Yamazaki, and S. Kakizawa. (2014). Contribution of calumin to embryogenesis through participation in the endoplasmic reticulum-associated degradation activity. Dev Biol 393: 33-43.
Examples:
TC#	Name	Organismal Type	Example
8.A.142.1.1	PAT heterodimeric complex consisting of two proteins, coiled-coil domain-containing (CCDC) protein, (CDCC47) of 483 aas and 1 N-terminal TMS, and possibly another TMS towards the C-terminus, and Asterix of 106 aas and 2 TMSs. Together they form the PAT chaparone complex in the endoplasmic reticulum (ER) that helps to properly insert multispanning membrane proteins into the ER membranes of eukaryotes (Chitwood and Hegde 2020). It is involved in the regulation of calcium ion homeostasis in the ER (Morimoto et al. 2018) and is required for proper protein degradation via the ERAD pathway (Yamamoto et al. 2014). It plays an essential role in the maintenance of ER organization during embryogenesis. The PAT complex engages early TMSs of multipass proteins to promote their biogenesis. The nascent chain is not engaged with Sec61, which is occluded and latched closed by CCDC47. Instead, Asterix binds to and redirects the substrate to a location behind Sec61, where the PAT complex contributes to a multipass translocon surrounding a semi-enclosed, lipid-filled cavity (Smalinskaitė et al. 2022).		PAT complex of Homo sapiens CCDC47, Q96A33 Asterix, Q9Y284

8.A.142.1.2	Coiled-coil domain-containing protein 47 (CCDC47) of 483 aas and 1 N-terminal TMS plus another possible TMS as well as an Asterix homolog of 103 aas and two TMSs. These two uncharacterized protein presumably comprise a PAT complex.		PAT complex of Echinococcus granulosus

8.A.142.1.3	Putative PAT complex consisting of a CCDC47 homolog of 490 aas and 1 - 3 TMSs, and an asterix-like isoform X1 protein of 118 aas and two TMSs.		PAT complex of Malus domestica CCDC47, XP_008347959.2 Asterix-like protein, XP_008374605.1

8.A.142.1.4	Uncharacterized pair of proteins, one of 377 aas and probably two TMSs, one N-terminal TMS and the other about a quarter of the way from the N-terminus, the other protein of 123 aas and two TMSs. These two proteins presumably form a PAT complex.		PAT complex of Tetrahymena thermophila CCDC47 homolog, XP_001015212.2 Asterix homolog, XP_001023376.

8.A.142.1.5	Uncharacterized putative PAT complex with two homologues of 387aas and 2 TMSs and 113 aas and 2 TMSs.		Two constituent PAT complex of Phytophthora megakarya