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Gene Review

LMAN1  -  lectin, mannose-binding, 1

Homo sapiens

Synonyms: ER-Golgi intermediate compartment 53 kDa protein, ERGIC-53, ERGIC53, F5F8D, FMFD1, ...
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Disease relevance of LMAN1

  • Combined factor V - factor VIII deficiency (F5F8D): Compound heterozygosity for two novel truncating mutations in LMAN1 in a consanguineous patient [1].
  • Their efficient secretion requires the membrane lectin ER Golgi intermediate compartment protein-53 (ERGIC-53) and its soluble luminal interaction partner multiple coagulation factor deficiency protein 2 (MCFD2), which form a cargo receptor complex in the early secretory pathway [2].
  • The putative nucleocapsid (p22) and envelope (gp35 and gp58) proteins have been expressed in cells by different vectors under various foreign promoters [3].
  • Fine specificity of the human immune response to the major neutralization epitopes expressed on cytomegalovirus gp58/116 (gB), as determined with human monoclonal antibodies [4].
  • Overexpression of Sar1(H79G) by transfection or by a novel recombinant vaccinia virus with an inducible Sar1(H79G) gene resulted in retention of ERGIC 53 in the ER but did not interfere with localization of viral primary membrane proteins in factory regions or with formation of viral crescent membranes and infectious intracellular mature virions [5].

High impact information on LMAN1

  • These findings suggest that the MCFD2-LMAN1 complex forms a specific cargo receptor for the ER-to-Golgi transport of selected proteins [6].
  • MCFD2 is localized to the ERGIC through a direct, calcium-dependent interaction with LMAN1 [6].
  • Here we show that inactivating mutations in MCFD2 cause F5F8D with a phenotype indistinguishable from that caused by mutations in LMAN1 [6].
  • We provide evidence here of long-term synaptic plasticity in a songbird forebrain area required for song learning, the lateral magnocellular nucleus of the anterior neostriatum (LMAN) [7].
  • Here we show that a cathepsin-Z-related glycoprotein binds to the recycling, mannose-specific membrane lectin ERGIC-53 [8].

Chemical compound and disease context of LMAN1

  • The open reading frame encodes a protein of 830 amino acids (93.2K) with the characteristics of a transmembrane glycoprotein and close similarity to the gp58/116 complex of human cytomegalovirus (HCMV) [9].

Biological context of LMAN1


Anatomical context of LMAN1

  • MCFD2 is a soluble EF-hand-containing protein that is retained in the endoplasmic reticulum through its interaction with LMAN1 [14].
  • ERGIC-53 is a lectin-like transport receptor protein, which recirculates between the ER and the Golgi complex and is required for the intracellular transport of a restricted number of glycoproteins [13].
  • Membranes enriched 110-fold over the homogenate for ERGIC-53 were obtained and analyzed by mass spectrometry [15].
  • Expression of a full-length cDNA of ERGIC-53 in Vero cells revealed intracellular localization similar but not always identical to the endogenously expressed ERGIC-53 [16].
  • If expressed in HeLa cells in a tetracycline-inducible manner, this mutant accumulated in the ER and retained the endogenous ERGIC-53 in this compartment, thus preventing its recycling [17].

Associations of LMAN1 with chemical compounds

  • LMAN1 is a type 1 transmembrane protein with homology to mannose-binding lectins [14].
  • Two mutations in LMAN1 have been observed in Jews: a guanine (G) insertion in exon 1 among Middle Eastern Jewish families, and a thymidine (T) to cytosine (C) transition in intron 9 at a donor splice site among Tunisian families [18].
  • Oligomerization and interacellular localization of the glycoprotein receptor ERGIC-53 is independent of disulfide bonds [19].
  • Previous results have shown that ERGIC-53 is present as reduction-sensitive homo-oligomers, i.e. as a balanced mixture of disulfide-linked hexamers and dimers, with the two cysteine residues located close to the transmembrane domain playing a crucial role in oligomerization [19].
  • Here, we demonstrate, using sucrose gradient sedimentation, cross-linking analyses, and non-denaturing gel electrophoresis, that ERGIC-53 is present exclusively as a hexameric complex in cells [19].

Physical interactions of LMAN1

  • Cargo binding properties of the ERGIC-53/MCFD2 complex were analyzed in vivo using yellow fluorescent protein fragment complementation [2].
  • The ER-Golgi intermediate compartment (ERGIC) marker ERGIC-53 is a mannose-specific membrane lectin operating as a cargo receptor for the transport of glycoproteins from the ER to the ERGIC [20].
  • The mannose lectin ERGIC-53 operates as a cargo receptor in transport of glycoproteins from ER to Golgi and the homologous lectin VIP36 may operate in quality control of glycosylation in the Golgi [21].

Other interactions of LMAN1

  • Previously, a requirement for a functional LMAN1 cycling pathway between the ER and Golgi was demonstrated for efficient secretion of FV and FVIII (Moussalli et al. J Biol Chem 1999; 274: 32569), however, the molecular nature of the interaction between LMAN1 and its cargo was not characterized [22].
  • Thapsigargin-induced upregulation of ERGIC-53 could be fully accounted for by the ATF6 pathway of UPR [23].
  • Mutation of the lectin domain of ERGIC-53 selectively decreased YFP complementation with cathepsin Z [11].
  • When expressed in Chinese hamster ovary cells, PLD1 localized to dispersed small vesicles that overlapped with the location of the ERGIC53 protein, a marker for the endoplasmic reticulum (ER)-Golgi intermediate compartment [24].
  • The results suggest that VIPL may function as a regulator of ERGIC-53 [25].

Analytical, diagnostic and therapeutic context of LMAN1


  1. Combined factor V - factor VIII deficiency (F5F8D): Compound heterozygosity for two novel truncating mutations in LMAN1 in a consanguineous patient. Farah, R.A., de Moerloose, P., Bouchardy, I., Morris, M.A., Barakat, W., Sayad, A.E., Neerman-Arbez, M. Thromb. Haemost. (2006) [Pubmed]
  2. Cargo Selectivity of the ERGIC-53/MCFD2 Transport Receptor Complex. Nyfeler, B., Zhang, B., Ginsburg, D., Kaufman, R.J., Hauri, H.P. Traffic (2006) [Pubmed]
  3. Structural proteins of hepatitis C virus. Miyamura, T., Matsuura, Y. Trends Microbiol. (1993) [Pubmed]
  4. Fine specificity of the human immune response to the major neutralization epitopes expressed on cytomegalovirus gp58/116 (gB), as determined with human monoclonal antibodies. Ohlin, M., Sundqvist, V.A., Mach, M., Wahren, B., Borrebaeck, C.A. J. Virol. (1993) [Pubmed]
  5. Evidence against an essential role of COPII-mediated cargo transport to the endoplasmic reticulum-Golgi intermediate compartment in the formation of the primary membrane of vaccinia virus. Husain, M., Moss, B. J. Virol. (2003) [Pubmed]
  6. Bleeding due to disruption of a cargo-specific ER-to-Golgi transport complex. Zhang, B., Cunningham, M.A., Nichols, W.C., Bernat, J.A., Seligsohn, U., Pipe, S.W., McVey, J.H., Schulte-Overberg, U., de Bosch, N.B., Ruiz-Saez, A., White, G.C., Tuddenham, E.G., Kaufman, R.J., Ginsburg, D. Nat. Genet. (2003) [Pubmed]
  7. Developmentally restricted synaptic plasticity in a songbird nucleus required for song learning. Boettiger, C.A., Doupe, A.J. Neuron (2001) [Pubmed]
  8. The lectin ERGIC-53 is a cargo transport receptor for glycoproteins. Appenzeller, C., Andersson, H., Kappeler, F., Hauri, H.P. Nat. Cell Biol. (1999) [Pubmed]
  9. The glycoprotein B homologue of human herpesvirus 6. Ellinger, K., Neipel, F., Foà-Tomasi, L., Campadelli-Fiume, G., Fleckenstein, B. J. Gen. Virol. (1993) [Pubmed]
  10. The locus for combined factor V-factor VIII deficiency (F5F8D) maps to 18q21, between D18S849 and D18S1103. Neerman-Arbez, M., Antonarakis, S.E., Blouin, J.L., Zeinali, S., Akhtari, M., Afshar, Y., Tuddenham, E.G. Am. J. Hum. Genet. (1997) [Pubmed]
  11. Capturing protein interactions in the secretory pathway of living cells. Nyfeler, B., Michnick, S.W., Hauri, H.P. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  12. ERGIC-53 gene structure and mutation analysis in 19 combined factors V and VIII deficiency families. Nichols, W.C., Terry, V.H., Wheatley, M.A., Yang, A., Zivelin, A., Ciavarella, N., Stefanile, C., Matsushita, T., Saito, H., de Bosch, N.B., Ruiz-Saez, A., Torres, A., Thompson, A.R., Feinstein, D.I., White, G.C., Negrier, C., Vinciguerra, C., Aktan, M., Kaufman, R.J., Ginsburg, D., Seligsohn, U. Blood (1999) [Pubmed]
  13. Heat shock induces preferential translation of ERGIC-53 and affects its recycling pathway. Spatuzza, C., Renna, M., Faraonio, R., Cardinali, G., Martire, G., Bonatti, S., Remondelli, P. J. Biol. Chem. (2004) [Pubmed]
  14. LMAN1 and MCFD2 form a cargo receptor complex and interact with coagulation factor VIII in the early secretory pathway. Zhang, B., Kaufman, R.J., Ginsburg, D. J. Biol. Chem. (2005) [Pubmed]
  15. Proteomics of endoplasmic reticulum-Golgi intermediate compartment (ERGIC) membranes from brefeldin A-treated HepG2 cells identifies ERGIC-32, a new cycling protein that interacts with human Erv46. Breuza, L., Halbeisen, R., Jenö, P., Otte, S., Barlowe, C., Hong, W., Hauri, H.P. J. Biol. Chem. (2004) [Pubmed]
  16. ERGIC-53, a membrane protein of the ER-Golgi intermediate compartment, carries an ER retention motif. Schindler, R., Itin, C., Zerial, M., Lottspeich, F., Hauri, H.P. Eur. J. Cell Biol. (1993) [Pubmed]
  17. Mistargeting of the lectin ERGIC-53 to the endoplasmic reticulum of HeLa cells impairs the secretion of a lysosomal enzyme. Vollenweider, F., Kappeler, F., Itin, C., Hauri, H.P. J. Cell Biol. (1998) [Pubmed]
  18. A mutation in LMAN1 (ERGIC-53) causing combined factor V and factor VIII deficiency is prevalent in Jews originating from the island of Djerba in Tunisia. Segal, A., Zivelin, A., Rosenberg, N., Ginsburg, D., Shpilberg, O., Seligsohn, U. Blood Coagul. Fibrinolysis (2004) [Pubmed]
  19. Oligomerization and interacellular localization of the glycoprotein receptor ERGIC-53 is independent of disulfide bonds. Neve, E.P., Lahtinen, U., Pettersson, R.F. J. Mol. Biol. (2005) [Pubmed]
  20. ERGIC-53 and traffic in the secretory pathway. Hauri, H.P., Kappeler, F., Andersson, H., Appenzeller, C. J. Cell. Sci. (2000) [Pubmed]
  21. Lectins and traffic in the secretory pathway. Hauri, H., Appenzeller, C., Kuhn, F., Nufer, O. FEBS Lett. (2000) [Pubmed]
  22. LMAN1 is a molecular chaperone for the secretion of coagulation factor VIII. Cunningham, M.A., Pipe, S.W., Zhang, B., Hauri, H.P., Ginsburg, D., Kaufman, R.J. J. Thromb. Haemost. (2003) [Pubmed]
  23. The cargo receptor ERGIC-53 is a target of the unfolded protein response. Nyfeler, B., Nufer, O., Matsui, T., Mori, K., Hauri, H.P. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  24. Phospholipase D as an effector for ADP-ribosylation factor in the regulation of vesicular traffic. Roth, M.G., Bi, K., Ktistakis, N.T., Yu, S. Chem. Phys. Lipids (1999) [Pubmed]
  25. Profile-based data base scanning for animal L-type lectins and characterization of VIPL, a novel VIP36-like endoplasmic reticulum protein. Nufer, O., Mitrovic, S., Hauri, H.P. J. Biol. Chem. (2003) [Pubmed]
  26. Mapping of the MR60/ERGIC-53 gene to human chromosome 18q21.3-18q22 by in situ hybridization. Arar, C., Mignon, C., Mattei, M., Monsigny, M., Roche, A., Legrand, A. Mamm. Genome (1996) [Pubmed]
  27. Evidence for a COP-I-independent transport route from the Golgi complex to the endoplasmic reticulum. Girod, A., Storrie, B., Simpson, J.C., Johannes, L., Goud, B., Roberts, L.M., Lord, J.M., Nilsson, T., Pepperkok, R. Nat. Cell Biol. (1999) [Pubmed]
  28. Targeting of protein ERGIC-53 to the ER/ERGIC/cis-Golgi recycling pathway. Itin, C., Schindler, R., Hauri, H.P. J. Cell Biol. (1995) [Pubmed]
  29. Molecular analysis of the ERGIC-53 gene in 35 families with combined factor V-factor VIII deficiency. Neerman-Arbez, M., Johnson, K.M., Morris, M.A., McVey, J.H., Peyvandi, F., Nichols, W.C., Ginsburg, D., Rossier, C., Antonarakis, S.E., Tuddenham, E.G. Blood (1999) [Pubmed]
  30. Development of intrinsic and synaptic properties in a forebrain nucleus essential to avian song learning. Livingston, F.S., Mooney, R. J. Neurosci. (1997) [Pubmed]
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