9.B.311 The 6-7 TMS TRAM/LAG (TRAM/LAG) Family This family is a large diverse family of proteins most frequently with about 220 - 300 aas and usually 6 or 7 TMSs, but variants occur, particularly larger homologues. They are found in many eukaryotes including animals, plants and fungi as well as lower eukaryotes, but they do not appear to occur in prokaryotes. TRAMs are sphingolipid-binding proteins (Zimmerli et al. 2021). The family includes members of diverse function and has been given many different names including Calfacilitin ( a modulator of Ca²⁺ L-type CA_V1.2 channel function), CLN8, Ceremide synthase, Sphingosine N-acyl transferase, TRAM/LAG1/CLN8-like, TLC-domain-containing protein, LAG1 longevity assurance protein, Fam57A, TMM57A, Fam56, 56B, 56C, 56X1, TMM56B, TMEM56C. TMEM56X1, TMM136 and DUF887. The name of the family used in TCDB refers to two domains in these proteins, the TRAM and the LAG domains.
References:
Chen, Q., B. Denard, C.E. Lee, S. Han, J.S. Ye, and J. Ye. (2016). Inverting the Topology of a Transmembrane Protein by Regulating the Translocation of the First Transmembrane Helix. Mol. Cell 63: 567-578.
Klein, M.C., M. Lerner, D. Nguyen, S. Pfeffer, J. Dudek, F. Förster, V. Helms, S. Lang, and R. Zimmermann. (2020). TRAM1 protein may support ER protein import by modulating the phospholipid bilayer near the lateral gate of the Sec61-channel. Channels (Austin) 14: 28-44.
Stefanovic, B., L. Stefanovic, B. Schnabl, R. Bataller, and D.A. Brenner. (2004). TRAM2 protein interacts with endoplasmic reticulum Ca²⁺ pump Serca2b and is necessary for collagen type I synthesis. Mol. Cell Biol. 24: 1758-1768.
Wang, H., A.P. Pang, W. Wang, B. Li, C. Li, F.G. Wu, and F. Lin. (2022). Discovery of ER-localized sugar transporters for cellulase production with lac1 being essential. Biotechnol Biofuels Bioprod 15: 132.
Zimmerli, C.E., M. Allegretti, V. Rantos, S.K. Goetz, A. Obarska-Kosinska, I. Zagoriy, A. Halavatyi, G. Hummer, J. Mahamid, J. Kosinski, and M. Beck. (2021). Nuclear pores dilate and constrict in cellulo. Science 374: eabd9776.
Examples:
TC#	Name	Organismal Type	Example
9.B.311.1.1	Protein FAM57A isoform X2 of 257 aas and 7 TMSs.		FAM57A protein of Piliocolobus tephrosceles

9.B.311.1.10	Transmembrane protein 136-like isoform X2 of 244 aas and 6 TM		136 of Acanthaster planci

9.B.311.1.11	Transmembrane protein 56 of 254 aas and 6 or 7 TMSs.		TMEM56 of Stylonychia lemnae

9.B.311.1.12	Transmembrane protein 136-like isoform X2 of 221 aas and 7 TMSs. It has TRAM, LAG1 and CLN8 (TLC) lipid-sensing domains.		TMEM136 of Durio zibethinus

9.B.311.1.13	TLC domain-containing protein 2 of 244 aas and 5 TM		TLC domain protein of Apteryx rowi

9.B.311.1.14	Uncharacterized TRAM/LAG1/CLN8-like domain-containing proteinof 672 aas and ~14 TMSs. This protein contains an internal repeat where TMSs 1 - 6 resemble TMSs 7-12.		UP of Artemisia annua

9.B.311.1.15	Uncharacterizxed protein of 435 aas and 7 TMSs		UP of Toxoplasma gondii

9.B.311.1.16	Uncharacterized protein of 269 aas and 6 TMSs.		UP of Paramecium tetraurelia

9.B.311.1.17	Transmembrane protein 56-like C of 167 aas and 6 TMSs		TMEM67 of Hondaea fermentalgiana

9.B.311.1.18	Uncharacterized protein of 381 aas and 7 TMSs in a 1 + 6 arrangement with a 150 aa hydrophilic domain between TMSs 1 and 2.		UP of Chlamydomonas reinhardtii

9.B.311.1.19	Ceramide synthase 6 isoform X1 of 381 aas and 7 TMSs.		Ceremide synthase of Lingula anatina

9.B.311.1.2	Protein FAM57A isoform 1 of 257 aas and 7 TMSs.		FAM57A protein of Homo sapiens

9.B.311.1.20	Ceramide synthase 1 of 274 aas and 6 TM		Ceramide synthase of Amphiprion ocellaris

9.B.311.1.21	LAG1 longevity assurance protein of 355 aas and 6 TMSs.		LAG1 of Oxytricha trifallax

9.B.311.1.22	Uncharacterized protein of 1573 aas and 6 C-terminal TMSs.		UP of Albugo candida

9.B.311.1.23	Uncharacterized TLC domain-containing protein 2 of 260 aas and 6 TMSs.		UP of Crassostrea gigas

9.B.311.1.24	Uncharacterized protein of 382 aas and 6 TMSs.		UP of Dictyostelium purpureum

9.B.311.1.25	Uncharacterized protein of 317 aas and ~ 7 TMSs.		UP of Thalassiosira oceanica

9.B.311.1.26	Uncharacterized protein of 276 aas and 6 TMSs.		UP of Oxytricha trifallax

9.B.311.1.27	Uncharacterized protein of 175 aas and 7 TMSs.		UP of Chondrus crispus (Carrageen Irish moss) (Polymorpha crispa)

9.B.311.1.28	Uncharacterized protein of 315 aas and 6 TMSs.		UP of Emiliania huxleyi

9.B.311.1.29	Sphingosine N-acyltransferase lac1of 452 aas and 6 TMSs.		N-acyltransferase of Leucoagaricus sp. SymC.cos

9.B.311.1.3	Uncharacterized protein of 323 aas and 6 or 7 TMSs.		UP of Glonium stellatum

9.B.311.1.30	Uncharacterized protein of 278 aas and 6 TMSs		UP of Caenorhabditis elegans

9.B.311.1.32	Sphingosine N-acyltransferase, lac1, of 475 aas and 7 TMSs in a 6 + 1 TMS arrangement. It may also be a sugar transporter, Lac1, in the ER. It is essential for cellulase production and biomass formation by affecting protein processing in the ER (particularly protein glycosylation) and lipid biosynthesis. The effect of LAC1 on cellulase production seems to be post-transcriptional at a late stage of cellulase production, independent on the well-known cellulase regulation mediated by CRT1 and XYR1 (Wang et al. 2022).		Lac1 of Trichoderma parareesei

9.B.311.1.4	Uncharacterized protein of 299 aas and 6 or 7 TMSs.		UP of Coccomyxa subellipsoidea

9.B.311.1.5	Uncharacterized protein of 287 aas and 6 or 7 TMSs.		UP of Galdieria sulphuraria

9.B.311.1.6	Transmembrane protein 56-B of 256 aas and 6 or 7 TM		TMEM56-A of Oryzias latipes

9.B.311.1.7	Transmembrane protein 56-like isoform X1of 271 aas and 6 TMSs.		TMEM56 of Brassica napus

9.B.311.1.8	Protein CLN8 of 285 aas and 7 TM		CLN8 of Columba livia

9.B.311.1.9	Calfacilitin isoform X2 of 248 aas and 6 TM		Calfacilitin of Lingula anatina

Examples:
TC#	Name	Organismal Type	Example
9.B.311.2.1	TRAM1 of 374 aas and 6 - 8 TMSs, possibly in a 3 + 3 TMS arrangement. The translocating chain-associated membrane protein (TRAM1) was proposed to support transport of a subset of protein precursors, but this may not be true (Klein et al. 2020). TRAM1 depletion did not affect calcium leakage from the ER. TRAM1 does not appear to affect the open probability of the Sec61-channel and may rather play a supportive role in protein transport, such as making the phospholipid bilayer conducive in the vicinity of the lateral gate of the Sec61-channel (Klein et al. 2020).		TRAM1 of Homo sapiens

9.B.311.2.2	Uncharacterized protein of 172 aas and 3 TMSs		UP of Brugia timori

9.B.311.2.3	TRAML1 of 369 aas and 3 TMSs		TRAML1 of Homo sapiens

9.B.311.2.4	Translocating chain-associated membrane protein 2, TRAM2, of 370 aas and 3 TMSs. It interacts with SERCA2b (Stefanovic et al. 2004). TRAM2 , a membrane protein containing a putative ceramide-interacting domain. It plays a role in membrane insertion of integral membrane proteins, influencing their topologies (Chen et al. 2016).		TRAM2 of Homo sapiens