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  • Review Article
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Sorting out the cellular functions of sorting nexins

Nature Reviews Molecular Cell Biology volume 3, pages 919–931 (2002)Cite this article

A Correction to this article was published on 01 February 2003

Key Points

  • Sorting nexins (SNXs) are 400–700 amino-acid hydrophilic proteins that are characterized by the presence of a phospholipid-binding domain, the PX domain. In addition to the PX domain, SNXs have various protein–protein interaction motifs that might determine their subcellular localization or their ability to form specific complexes.

  • On the basis of common domain structures, the SNX family of proteins can be divided into three subgroups. The first group, which contains SNX1 and SNX2, has long carboxy-terminal extensions containing 1–3 coiled-coil domains that might be involved in homo- and/or hetero-oligomerization with other SNXs, as well as other protein–protein interactions. The second group is formed by SNX3 and related SNXs, which seem to have only a PX domain. The remaining SNXs, which form the third group, have a variety of protein–protein interaction, membrane targeting or G-protein regulatory sequences.

  • The structure of the PX domain of p40phox revealed a novel protein fold and mutational analysis identified several residues that are involved in stabilizing the binding of PtdIns(3)P to p40phox. Studies of the structure of the p47phox PX domain showed that SH3-domain interactions might regulate PX-domain function. Structural analysis of the PX domain of Vam7 showed that the membrane-targeting ability of the Vam7 PX domain might involve both a specific basic PtdIns-binding pocket, as well as nonspecific hydrophobic interactions between loop residues and the membrane.

  • The functions of yeast nexins are relatively well established. Vps5, the yeast homologue of SNX1 and SNX2, is important for vacuolar trafficking and carries out its function by assembling into a so-called retromer complex. Grd19, which is related to SNX3, seems to have a function in the pre-vacuolar compartment. Mvp1, the yeast homologue for SNX8, might be involved in sorting proteins in the late Golgi for delivery to the vacuole, as well as the retrieval of proteins from the pre-vacuolar endosomes to the late Golgi.

  • Mammalian SNXs are thought to be important for the sorting of proteins in the endosomal pathway but possibly also in sorting vesicles that are not derived from the plasma membrane. The challenge for future research will be to identify the specific functions of individual SNXs, and to study the cellular regulation of these molecules.

Abstract

Sorting nexins are a diverse group of cellular trafficking proteins that are unified by the presence of a phospholipid-binding motif — the PX domain. The ability of these proteins to bind specific phospholipids, as well as their propensity to form protein–protein complexes, points to a role for these proteins in membrane trafficking and protein sorting. It will be interesting to determine whether the various sorting nexins have specialized or generalized roles in protein trafficking.

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Figure 1: Protein and membrane trafficking.
Figure 2: Human sorting nexins.
Figure 3: PX-domain phylogenetic tree.
Figure 4: Crystal structure of the p40phox domain.
Figure 5: SNX-PX domain alignment.
Figure 6: The functions of the sorting nexins.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Protein Data Bank

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Acknowledgements

Many thanks go to R. Holz and N. Leff for their critical reading of this manuscript, and to M. Wishart for his critical reading and help with the phylogeny study. J. Stuckey's help with the p40phox structure was much appreciated.

Author information

Authors and Affiliations

  1. Department of Biological Chemistry, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Carolyn A. Worby & Jack E. Dixon

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  1. Carolyn A. Worby
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  2. Jack E. Dixon
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Correspondence to Carolyn A. Worby.

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DATABASES

Swiss-Prot

Grd19

Mvp1

p40phox

p47phox

SNX1

SNX2

SNX3

SNX4

SNX5

SNX6

SNX9

SNX13

SNX15

SNX17

Vam7

Vps5

FURTHER INFORMATION

Jack E. Dixon's laboratory

Expasy

SMART

Glossary

CLATHRIN-COATED VESICLE

A vesicle that is coated with clathrin, which is a protein able to self-assemble into triskelions (three-legged pinwheels) that coalesce with specific adaptor proteins (APs) to form a polyhedral lattice. Endocytosed vesicles are often coated with the clathrin–AP2 complex.

EARLY ENDOSOME

Irregularly shaped and mildly acidic intracellular vesicle that is formed from an endocytosed clathrin-coated vesicle.

LYSOSOME

The cellular compartment where the digestion of proteins and other materials occurs.

LATE ENDOSOME

The acidic vesicle formed from an early endosome where proteins are either sorted for transport to the trans-Golgi network or for digestion in the lysosome. They function as the precursor vesicles for mature lysosomes.

TRANS-GOLGI NETWORK

(TGN). Membranous compartment from which vesicles bud to deliver proteins and other materials to the cell surface or to the late endosomes for delivery to lysosomes.

SORTING NEXIN

(SNX). A hydrophilic protein of 400–700 amino acids that contains a PX domain in the middle or amino-terminal half of the protein and regions of predicted coiled coils in the carboxy-terminal half of the protein. It functions in the endocytosis of plasma-membrane receptors and/or the trafficking of proteins from one membrane compartment to another.

PX DOMAIN

(phox homology domain). A lipid- and protein-interaction domain that consists of 100–130 amino acids and is defined by sequences found in two components of the phagocyte NADPH oxidase (phox) complex.

COILED-COIL DOMAIN

A bundle of α-helices that are wound into a superhelix. Coiled coils were first described as the main structural element of a large class of fibrous proteins, which includes keratin, myosin and fibrinogen.

SH3 DOMAIN

(Src homology 3 domain). A protein–protein interaction domain of ∼60 amino acids that binds to proline-rich (Pro-X-X-Pro) sequences.

TPR DOMAIN

(tetratricopeptide repeat). This domain typically consists of 34 amino acids and probably functions as a protein–protein interaction motif. It is commonly found in proteins that aggregate in multi-protein complexes.

B41 DOMAIN

(Band 4.1 homology domain, also known as an ezrin/radixin/moesin (ERM) protein domain). This domain is commonly found in cytoskeletal-associated proteins, linking these proteins to the plasma membrane.

RGS DOMAIN

(regulator of G-protein-signalling domain). A sequence of ∼120 amino acids that functions as a GTPase activator that stimulates the inactivation of heterotrimeric G proteins, thereby rapidly turning off G-protein-coupled-receptor signalling pathways.

RA DOMAIN

(RasGTP effector domain). Stimulates the dissociation of GDP from Ras-related proteins, thereby allowing the binding of GTP and activation of the GTPases.

EPSIN AMINO (N)-TERMINAL HOMOLOGY DOMAIN

(ENTH). A phospholipid-binding motif with high affinity for PtdIns(4,5)P2.

PLEXTRIN-HOMOLOGY DOMAIN

(PH). A phospholipid-binding motif that interacts with many different phospholipids including PtdIns(3,4,5)P3, PtdIns(4,5)P2 and PtdIns(3,4)P2.

FYVE DOMAIN

(Fab1/YOTB/Vac1/EEA1 domain). A phospholipid-binding motif that interacts exclusively with PtdIns(3)P.

EARLY ENDOSOMAL AUTO-ANTIGEN 1

(EEA1). A FYVE-domain-containing protein that is commonly used as a marker for early endosomes. This protein is an autoantigen that is associated with subacute cutaneous systemic lupus erythematosis.

SNX-PX DOMAIN

The classification for the PX domains that are found in sorting nexins and that participate in lipid–protein and/or protein–protein interactions.

SNARE

(soluble N-ethylmaleimide-sensitive factor attachment protein receptor). SNAREs are proteins that are involved in membrane-fusion events in the secretory and endocytic pathways. SNAREs contain coiled-coil domains that form tight four-helix bundles, which are proposed to drive membranes into close apposition ready for fusion.

LYSOSOMAL TARGETING SEQUENCE

There are two types of lysosomal targeting sequences: the tyrosine-based sequence, which consists of a tyrosine residue followed by a hydrophobic (Hyd) residue three amino acids later (Tyr-X-X-Hyd), and the di-leucine repeat (LL). Usually more than one of these targeting sequences is found in proteins that are destined for the lysosome.

AP2

This adaptor protein complex is a component of clathrin-coated vesicles that are associated with the plasma membrane. The complex is heterotetrameric with two large subunits, α and β2, a medium-sized μ-subunit and a small σ-subunit. AP-50 is the Drosophila equivalent of the μ-subunit that has been implicated in cargo selection.

ENDOSOMAL RETENTION

A mechanism that traps specific proteins inside the endosomal compartment, thereby preventing recycling of the protein to the cell surface.

HRS

A FYVE-domain-containing protein that is localized to early endosomes. HRS contains a clathrin-binding motif as well as a ubiquitin-interaction motif and can therefore affect the sorting of ubiquitylated proteins into the clathrin-coated microdomains of early endosomes.

TGF-β RECEPTOR SUPERFAMILY

Receptors in this superfamily are activated by numerous peptide ligands including TGF-β, actinin/inhibin, bone morphogenetic proteins, growth and differentiation factors, glial-derived neurotrophic factor and Mullerian inhibitory substance. The receptors for this superfamily fall into two categories: type II (Ser/Thr kinases), which bind ligand, and type I, which, following recruitment and subsequent phosphorylation by the type II receptor, transduces the signal to the cell.

RECYCLING ENDOSOMES

Vesicles that are derived from early endosomes destined for fusion with the plasma membrane.

G-PROTEIN-COUPLED RECEPTORS

(GPCR). Receptors that span the seven-transmembrane domain and that, on ligand stimulation, activate small G proteins by facilitating the exchange of GDP for GTP.

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Worby, C., Dixon, J. Sorting out the cellular functions of sorting nexins. Nat Rev Mol Cell Biol 3, 919–931 (2002). https://doi.org/10.1038/nrm974

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