9.A.27 The Non-Classical Protein Exporter (NCPE) Family

Several physiologically important proteins in eukaryotes lack a classical secretory signal sequence but are secreted. Mammalian galectin-1 expressed in S. cerevisiae is exported across the yeast plasma membrane in a process that does not require the Sec (3.A.5) or Ste6p (3.A.1.206.1) system (Cleves et al., 1997). One study suggests an involvement of lipid rafts (Broquet et al., 2003). Nce102 may be an accessory subunit to an essential core component of the non-classical protein export machinery. Alternatively, its role in export may be indirect. 

Fibroblast Growth Factor 2 (FGF2) has been reported to be post-translationally secreted across the plasma membranes of mammals in a process that is independent of the endoplasmic reticulum/golgi general secretion (TC #3.A.5) system. This novel system has been reconstituted in vitro in plasma membrane inside-out vesicles (Schäfer et al., 2004) and does not require ATP. Secretion of FGF2 is unidirectional and requires both integral and peripheral membrane proteins. Galectin-1 is also transported by this mechanism. More than one such process may occur (Schäfer et al., 2004). No sequence data for proteins that comprise the system are available.

Two genes (NCE1 and NCE2) involved in the NCPE pathway have been cloned from S. cerevisiae, and their products have homologues in other fungi (Cleves et al., 1996). NCE2 (173 aas) has 4 putative TMSs and may be homologous to mouse synaptogyrin (O55100; 234 aas) which also has 4 TMSs (Kedra et al., 1998). NCE1 has 53 aas.

The plasma membrane of the yeast Saccharomyces cerevisiae contains stably distributed lateral domains of specific composition and structure, termed MCC (membrane compartment of arginine permease, Can1). Accumulation of Can1 and other specific proton symporters within MCC is known to regulate the turnover of these transporters and is controlled by the presence of another MCC protein, Nce102. Loibl et al. (2010) showed that in an NCE102 deletion strain, the function of Nce102 in directing the specific permeases into MCC can be complemented by overexpression of the NCE102 homolog, FHN1 (the previously uncharacterized YGR131W protein) as well as by distant Schizosaccharomyces pombe homolog fhn1 (SPBC1685.13). This mechanism of plasma membrane organization appears to be conserved through the phylum Ascomycota. The N and C termini of Nec102 are oriented toward the cytosol. Deletion of the C terminus or even of the last 6 amino acids does not disturb protein trafficking, but it seriously affects the formation of MCC. The C-terminal part of Nce102 is necessary for localization of both Nce102 itself and Can1 to MCC and also for the formation of furrow-like membrane invaginations, the characteristic ultrastructural feature of MCC domains (Loibl et al., 2010).

This family belongs to the Tetraspan Junctional Complex Protein or MARVEL (4JC) Superfamily.



Broquet, A.H., G. Thomas, J. Masliah, G. Trugnan, and M. Bachelet. (2003). Expression of the molecular chaperone Hsp70 in detergent-resistant microdomains correlates with its membrane delivery and release. J. Biol. Chem. 278: 21601-21606.

Cleves, A.E., D.N.W. Cooper, S.H. Barondes, and R.B. Kelly. (1996). A new pathway for protein export in Saccharomyces cerevisiae. J. Cell Biol. 133: 1017-1026.

Iwamoto, M., H. Shimizu, I. Muramatsu, and S. Oiki. (2010). A cytotoxic peptide from a marine sponge exhibits ion channel activity through vectorial-insertion into the membrane. FEBS Lett. 584: 3995-3999.

Kedra, D., H.Q. Pan, E. Seroussi, I. Fransson, C. Guilbaud, J.E. Collins, I. Dunham, E. Blennow, B.A. Roe, F. Piehl, and J.P. Dumanski. (1998). Characterization of the human synaptogyrin gene family. Hum. Genet. 103: 131-141.

Loibl, M., G. Grossmann, V. Stradalova, A. Klingl, R. Rachel, W. Tanner, J. Malinsky, and M. Opekarová. (2010). C terminus of Nce102 determines the structure and function of microdomains in the Saccharomyces cerevisiae plasma membrane. Eukaryot. Cell. 9: 1184-1192.

Schäfer, T., H. Zentgraf, C. Zehe, B. Brügger, J. Bernhagen, and W. Nickel. (2004). Unconventional secretion of fibroblast growth factor 2 is mediated by direct translocation across the plasma membrane of mammalian cells. J. Biol. Chem. 279: 6244-6251.


TC#NameOrganismal TypeExample

The non-classical protein exporter (NCPE or Nce102) (Loibl et al., 2010)

Yeast, animals

NCPE of Saccharomyces cerevisiae
NCE1 (53 aas) (AAC49349)
NCE2 (173 aas) (AAB05589)



YGR131w, functional homologue of Nce102 (174 aas; 56% identical to Nce102) (Loibl et al., 2010).


YGR131w of Saccharomyces cerevisiae (P53279)


Fhl1 (SPBC1685) (183 aas) (Loibl et al., 2010).


Fhl1 of Schizosaccharomyces pombe (O74333)


Uncharacterized protein of 157 aas and 4 TMSs


UP of Aspergillus clavitus


Uncharacterized protein of 305 aas and 4 TMSs


UP of Lodderomyces (Saccharomyces) elongisporus


Uncharacterized protein of 189 aas and 4 TMSs


UP of Neurospora crassa


Uncharacterized protein of 170 aas and 4 TMSs


UP of Neurospora crassa