| 1.A.64 The Plasmolipin (Plasmolipin) Family
Plasmolipin (PLLP) is an 18-kDa proteolipid or lipoprotein found in kidney and brain, where it is restricted to the apical surface of tubular epithelial cells and to mammalian myelinated tracts, respectively. This protein is made during sciatic nerve development and regeneration in the rat. It has 182 aas and 4 TMSs (Fischer and Sapirstein, 1994). Addition of plasmolipin to lipid bilayers induces the formation of ion channels, which are voltage-dependent and K+-selective (Tosteson and Sapirstein, 1981). PLLP functions in myelin biogenesis through organization of myelin
liquid-ordered membranes in the Golgi complex (Yaffe et al. 2015).
Plasmolipin has many homologues. These are referred to as CKLF-like MARVEL transmembrane domain containing protein, chemokine-like factor and T-cell differentiation marker (Mitsugumin and Synaptogyrin). Most are about 180 - 210 residues, but several are about twice as large with 8 TMSs and an internal repeat (e.g., the myeloid-associated differentiation marker of humans (MAL or MYADM; Q96S97) or the rat (EAL84950). Synthesis of these proteins is induced by retinoic acid (Cui et al., 2001).
Plasmolipin localizes to and recycles between the plasma membrane and the Golgi
complex. In the Golgi complex, it forms oligomers which
block Golgi to plasma membrane transport of the secretory
vesicular stomatitis virus G protein (VSVG) (Yaffe et al. 2015). Homologues, CMTM2A and 2B, (TC# 1.A.64.5.6 and 5.7, respectively) are required for male fertility (Fujihara et al. 2018).
The transport reaction that occurs with plasmolipin in artificial membranes is:
Ions (in)  Ions (out)
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This family belongs to the Tetraspan Junctional Complex Protein or MARVEL (4JC) Superfamily.
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| References: |
Carmosino, M., F. Rizzo, G. Procino, D. Basco, G. Valenti, B. Forbush, N. Schaeren-Wiemers, M.J. Caplan, and M. Svelto. (2010). MAL/VIP17, a New Player in the Regulation of NKCC2 in the Kidney. Mol. Biol. Cell 21: 3985-3997.
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Cui W., L. Yu, H. He, Y. Chu, J. Gao, B. Wan, L. Tang, S. Zhao. (2001). Cloning of human myeloid-associated differentiation marker (MYADM) gene whose expression was up-regulated in NB4 cells induced by all-trans retinoic acid. Mol Biol Rep. 28(3): 123-138.
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Fischer I. and V.S. Sapirstein. (1994). Molecular cloning of plasmolipin. Characterization of a novel proteolipid restricted to brain and kidney. J. Biol. Chem. 269: 24912-24919.
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Fujihara, Y., A. Oji, K. Kojima-Kita, T. Larasati, and M. Ikawa. (2018). Co-expression of sperm membrane proteins CMTM2A and CMTM2B is essential for ADAM3 localization and male fertility in mice. J Cell Sci 131:.
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Hartzell, H.C., Z. Qu, K. Yu, Q. Xiao, and L.T. Chien. (2008). Molecular physiology of bestrophins: multifunctional membrane proteins linked to best disease and other retinopathies. Physiol. Rev. 88: 639-672.
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Li, D., C. Jin, C. Yin, Y. Zhang, B. Pang, L. Tian, W. Han, D. Ma, and Y. Wang. (2007). An alternative splice form of CMTM8 induces apoptosis. Int J Biochem. Cell Biol. 39: 2107-2119.
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Mezzadra, R., C. Sun, L.T. Jae, R. Gomez-Eerland, E. de Vries, W. Wu, M.E.W. Logtenberg, M. Slagter, E.A. Rozeman, I. Hofland, A. Broeks, H.M. Horlings, L.F.A. Wessels, C.U. Blank, Y. Xiao, A.J.R. Heck, J. Borst, T.R. Brummelkamp, and T.N.M. Schumacher. (2017). Identification of CMTM6 and CMTM4 as PD-L1 protein regulators. Nature 549: 106-110.
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Miyazaki, A., S. Yogosawa, A. Murakami, and D. Kitamura. (2012). Identification of CMTM7 as a transmembrane linker of BLNK and the B-cell receptor. PLoS One 7: e31829.
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Rubio-Ramos, A., L. Labat-de-Hoz, I. Correas, and M.A. Alonso. (2021). The MAL Protein, an Integral Component of Specialized Membranes, in Normal Cells and Cancer. Cells 10:.
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Steed, E., N.T. Rodrigues, M.S. Balda, and K. Matter. (2009). Identification of MarvelD3 as a tight junction-associated transmembrane protein of the occludin family. BMC Cell Biol 10: 95.
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Tosteson, M.T. and V.S. Sapirstein. (1981). Protein interactions with lipid bilayers: the channels of kidney plasma membrane proteolipids. J. Membr. Biol. 63: 77-84.
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Yaffe, Y., I. Hugger, I.N. Yassaf, J. Shepshelovitch, E.H. Sklan, Y. Elkabetz, A. Yeheskel, M. Pasmanik-Chor, C. Benzing, A. Macmillan, K. Gaus, Y. Eshed-Eisenbach, E. Peles, and K. Hirschberg. (2015). The myelin proteolipid plasmolipin forms oligomers and induces liquid-ordered membranes in the Golgi complex. J Cell Sci 128: 2293-2302.
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Zhou, J., J. Lei, J. Wang, C.L. Lian, L. Hua, Z.Y. He, and S.G. Wu. (2019). Bioinformatics-Based Discovery of -Like Transmembrane Member 5 as a Novel Biomarker for Breast Cancer. Front Cell Dev Biol 7: 361.
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| Examples: |
| TC# | Name | Organismal Type | Example |
| 1.A.64.1.1 | Channel-forming Plasmolipin (Fischer and Sapirstein, 1994) | Animals | Plasmolipin of Rattus norvegicus (P47987) |
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| 1.A.64.1.2 | Plasmolipin, PllP, or MARVEL domain-containing protein of 173 aas and 4 TMSs. | | PllP of Taeniopygia guttata (Zebra finch) (Poephila guttata) |
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| Examples: |
| TC# | Name | Organismal Type | Example |
| 1.A.64.2.1 | Myelin and Lymphocyte Protein, MAL/VIP17 protein, a regulator of NKCC2 (2.A.30.1.1). It stabilizes kidney apical membranes, and facilitates sorting of proteins to these membranes (Carmosino et al., 2010). It has 4 TMSs that align with those of plasmolipin. | Mammals | MAL/VIP17 of Canis familiaris (Q28296) |
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| 1.A.64.2.2 | Myelin and lymphocyte protein, MAL, of 153 aas and 4 TMSs. This human ortholog is 88% identical to the dog protein, TC# 1.A.64.2.1. It may be a component in vesicular
trafficking cycling between the Golgi complex and the apical plasma
membrane, and could be involved in myelin biogenesis and/or myelin function. It (1) has lipid-like properties that qualify it as a member of the group of proteolipid proteins. (2) it partitions selectively into detergent-insoluble membranes, consistent with MAL being distributed in highly ordered membranes in the cell. The structure, expression and biochemical characteristics of MAL, the association of MAL with raft membranes and the function of MAL in polarized epithelial cells have been discussed (Rubio-Ramos et al. 2021).
| | MAL of Homo sapiens |
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| 1.A.64.2.3 | T-cell differentiation protein A, MAL, of 163 aas and 4 TMSs. | | MAL of Tetraodon nigroviridis (Spotted green pufferfish) (Chelonodon nigroviridis) |
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| Examples: |
| TC# | Name | Organismal Type | Example |
| 1.A.64.3.1 | Myeloid-associated differentiation marker, MyADM (322 aas; 8 TMSs) | Animals | MyADM of Homo sapiens (Q96S97) |
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| 1.A.64.3.2 | Uncharacterized protein of 299 aas and 8 TMSs. | | UP of Ovis aries (Sheep) |
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| Examples: |
| TC# | Name | Organismal Type | Example |
| 1.A.64.4.1 | 4 TMS MARVEL superfamily member | Animals | 4TMS homologue of Caenorhabditis elegans (P83387) |
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| 1.A.64.4.2 | Uncharacterized MARVEL domain-containing protein of 174 aas and 3 TMSs. | | UP of Tetranychus urticae (Two-spotted spider mite) |
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| 1.A.64.4.3 | MARVEL domain-containing protein of 192 aas and 4 TMSs. | | MARVEL protein of Strigamia maritima (European centipede) (Geophilus maritimus) |
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| 1.A.64.4.4 | CKLF-like MARVEL transmembrane domain-containing protein 4, CMTM4, of 234 aas and 4 TMSs. It acts as a backup for CMTM6 to regulate plasma
membrane expression of PD-L1/CD274, an immune inhibitory ligand critical
for immune tolerance to self and antitumor immunity (Mezzadra et al. 2017). | | CMTM4 of Homo sapiens |
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| Examples: |
| TC# | Name | Organismal Type | Example |
| 1.A.64.5.1 | CKLF-like MARVEL transmembrane domain-containing protein 7, CMTM7 (175aas; 4 TMSs; Miyazaki et al., 2012). CMTM7 functions to link sIgM and BLNK in the plasma membrane, to recruit BLNK to the vicinity of Syk, and to initiate BLNK-mediated signal transduction (Miyazaki et al., 2012). No transport function is known. | Animals | CMTM7 of Homo sapiens (Q96FZ5) |
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| 1.A.64.5.2 | Proteolipid protein 2 (Differentiation-dependent protein A4) (Intestinal membrane A4 protein) | Animals |
A4 protein of Homo sapiens |
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| 1.A.64.5.3 | Uncharacterized protein of 208 aas | Animals | UP of Caenorhabditis elegans |
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| 1.A.64.5.4 | CKLF-like MARVEL transmembrane domain-containing protein 8 of 343 aas and 4 TMSs, CMTM8. A short splice variant, CMTM8-v2, retains the ability to induce apoptosis via caspase-dependent and
-independent pathways to inhibit cell growth and colony formation. CMTM8 and CMTM8-v2 display
different expression profiles and distinct subcellular localization patterns, while operating via
different mechanisms to induce apoptosis. CMTM8-v2 does not affect EGFR internalization, implying
that the MARVEL domain and/or the cytosolic YXXPhi motifs are necessary for CMTM8 to accelerate
ligand-induced EGFR internalization (Li et al. 2007). | | CMTM8 of Anas platyrhynchos (Mallard) (Anas boschas) |
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| 1.A.64.5.5 | CKIF-like MARVEL transmembrane domain containing protein 1 of 169 aas and 4 TMSs, CMTM1, or chemokine-like factor superfamily member 1, of 169 aas and 4 TMSs.
It is not required for mouse fertility although CMTM2A (TC# 1.A.64.5.6) and CMTM2B (TC#1.A.64.5.7 are
required (Fujihara et al. 2018). | | CMTM1 of Homo sapiens |
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| 1.A.64.5.6 | CKIF-like MARVEL transmembrane domain containing protein, CMTM2A of 169 aas and 4 TMSs, also called chemokine-like factor superfamily member 2A.
It and CMTM2B (TC#1.A.64.5.7) are required for mouse fertility although CMTM1 (TC# 1.A.64.5.5) is not required (Fujihara et al. 2018). | | CMTM2A of Mus musculus |
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| 1.A.64.5.7 | CKIF-like MARVEL transmembrane domain containing protein, CMTM2B of 210
aas and 4 TMSs, also called chemokine-like factor superfamily member
2B.
It and CMTM2A (TC#1.A.64.5.6) are required for mouse fertility although CMTM1 (TC# 1.A.64.5.5) is not required (Fujihara et al. 2018). | | CMTM2B of Mus musculus |
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| 1.A.64.5.8 | CKLF-Like MARVEL Transmembrane Member 5, CMTM5, or Chemokine-like factor superfamily member 5, of 223 aas and 4 or 5 TMSs. CMTM5 associates with pathways in MARVEL domains, chemotaxis, cytokines, transmembrane structures, and integral component of membrane (Zhou et al. 2019). | | CMTM5 of Homo sapiens |
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| Examples: |
| TC# | Name | Organismal Type | Example |
| 1.A.64.6.1 | Marvel D3 tight junction-associated occludin of 401 aas and 4 TMSs; a determinant of paracellular permeability (Steed et al. 2009). | Animals | MarvelD3 of Homo sapiens |
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| 1.A.64.6.2 | MARVEL domain containing 3, MARVELD3, of 314 aas and 4 TMSs, within the C-terminal half of the protein. | | MARVELD3 of Myotis lucifugus (Little brown bat) |
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