Abstract
Ice2p is an integral endoplasmic reticulum (ER) membrane protein in budding yeast S. cerevisiae named ICE because it is required for Inheritance of Cortical ER. Ice2p has also been reported to be involved in an ER metabolic branch-point that regulates the flux of lipid either to be stored in lipid droplets or to be used as membrane components. Alternately, Ice2p has been proposed to act as a tether that physically bridges the ER at contact sites with both lipid droplets and the plasma membrane via a long loop on the protein's cytoplasmic face that contains multiple predicted amphipathic helices. Here we carried out a bioinformatic analysis to increase understanding of Ice2p. First, regarding topology, we found that diverse members of the fungal Ice2 family have 10 transmembrane helices (TMHs), which places the long loop on the exofacial face of Ice2p, where it cannot form inter-organelle bridges. Second, we identified Ice2p as a full-length homolog of SERINC (serine incorporator), a family of proteins with 10 TMHs found universally in eukaryotes. Since SERINCs are potent restriction factors for HIV and other viruses, study of Ice2p may reveal functions or mechanisms that shed light on viral restriction by SERINCs.
Highlights
Many functions of membrane proteins remain far more mysterious than their soluble counterparts largely because the hydrophobic environment is hard to probe
Discoveries here include finding topological features that indicate a limited range of functions, identifying homologies where sequence has diverged below the threshold required for conventional tools, and defining the arrangement of transmembrane helices (TMHs) from ab initio modeling based on pairwise evolution of contacting side-chains.[4]
To determine the most likely topology of Ice2p, we considered that the topology was highly likely to be conserved across the whole family of proteins related to Ice2p, known as protein family PF08426, with single proteins per fungal species in all dikarya (Ascomycota and Basidiomycota), but absent from most Mucormycota and all Chytridiomycota, Zoopagomycota, and Microsporidia.[41]
Summary
Many functions of membrane proteins remain far more mysterious than their soluble counterparts largely because the hydrophobic environment is hard to probe. Ice2p is a multi-spanning endoplasmic reticulum (ER) localized yeast protein of 491 residues that was first named for its role in inheritance of cortical ER from mother to daughter cells.[5] Cortical ER is reduced in buds upon deletion of ICE2 alone,[5] and it is markedly reduced in both mother and daughter cells by deleting ICE2 in strains already carrying other mutations that reduce cortical ER.[6,7] The molecular function of Ice2p is unknown and genetic interactions implicate a wide range of ER-related activities These include an indirect effect on protein targeting to the inner nuclear envelope,[8,9] roles in stabilizing ER membrane proteins and in ER-associated degradation,[10,11,12] and supporting the function of some ER membrane proteins.[13]. We found that Ice2p is a full-length homolog of SERINCs, a ubiquitous eukaryotic family of proteins with 10 TMHs, named for their possible role in serine incorporation into lipids, and best known for their role as potent restriction factors for HIV and other viruses.[20,21] Given the conserved elements identified in a cryo-electron microscopy structure of SERINC,[22] this allowed us to identify likely key functional residues in Ice2p that can inform future experiments
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