QUICK SEARCH:   [advanced] Author: Keyword(s):
Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents

First published online July 25, 2006
doi: 10.1242/10.1242/jcs.03072

This Article Summary Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Odorizzi, G. Search for Related Content PubMed PubMed Citation Articles by Odorizzi, G.

The multiple personalities of Alix

Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309-0347, USA

View larger version (51K): [in a new window]   Fig. 1. Overview of the cellular mechanisms involving Alix. For clarity, growth factor receptors and viral components have been omitted, trafficking from the plasma membrane to endosomes is represented by two arrows, and focal adhesions are oversimplified. Fusion of the endosomal/MVB limiting membrane with the lysosome membrane results in the degradation of lumenal MVB vesicles by lysosomal hydrolases. Note that the association of Alix with endosomes appears to be important for its role in apoptotic signaling.

View larger version (22K): [in a new window]   Fig. 2. Schematic diagram depicting the domain organization of Alix and its family members in yeast, Bro1 and Rim20. Alix in humans contains 868 amino acid residues and is 94% identical to mouse Alix, which has 869 residues. Bro1 is similar in length (844 residues) and domain organization, whereas Rim20 is shorter (661 residues) and lacks a C-terminal proline-rich (Pro) region. Based upon the structure of the Bro1 domain in Bro1 (Kim et al., 2005), the Bro1 domains of Alix and Rim20 are predicted to span residues 1-366 and 1-387, respectively. Two putative coiled-coil domains (CC) are located between residues 430-471 and residues 543-583 of Alix, whereas Bro1 and Rim20 are each predicted to have a single CC domain between residues 543-583 (in Bro1) and 386-426 (in Rim20). The proline-rich region of Alix has the majority of protein-binding sites that link it to various cellular mechanisms (see Table 1 for details on specific amino acids involved in protein interactions). Similarly, the proline-rich region of Bro1 is contained within a region required for interaction with Doa4 (Kim et al., 2005). The C-terminal region of Rim20 binds the Rim101 transcription factor (Xu and Mitchell, 2001).

View larger version (41K): [in a new window]   Fig. 3. Alix and its binding partners in ESCRT-mediated protein sorting. For simplicity, components of the ESCRT machinery not known to bind Alix are omitted. Recruitment of Alix to the site of MVB sorting is mediated by the CHMP4 subunit of ESCRT-III, which binds directly to the Bro1 domain. It is not known whether CHMP4 has a similar role in recruiting Alix to the site of viral budding at the plasma membrane, nor is it known whether recruitment of Alix to either endosomes or the plasma membrane is facilitated by the TSG101 subunit of ESCRT-I. The wavy line connecting ESCRT-III to the membrane represents N-myristoylation of CHMP6, another subunit of ESCRT-III. Alix is depicted as a bridging factor between ESCRT-I and ESCRT-III, but whether Alix binds simultaneously to both complexes is not known. Note that several viruses use the ESCRT machinery to bud into endosomes and are then released from infected cells upon fusion of the endosomal membrane with the plasma membrane (reviewed by Morita and Sundquist, 2004). See text for further details. Ub, ubiquitin.

View larger version (68K): [in a new window]   Fig. 4. The Bro1 domain from the yeast Bro1 protein. (A) Ribbon diagram of the Bro1 domain. (B) Molecular surface of the Bro1 domain colored according to residue conservation, orange and red representing amino acids that are similar and identical, respectively, among orthologues of Bro1. Reproduced with permission from Elsevier (Kim et al., 2005).

View larger version (32K): [in a new window]   Fig. 5. Model for the negative regulation of EGFR endocytosis by Alix. For simplicity, activated EGFR is represented as a monomer rather than a dimer. (A) Alix inhibits association of the SETA-endophilin complex with Cbl and reduces Cbl-mediated ubiquitylation of EGFR, SETA and Cbl itself (Schmidt et al., 2004). Thus, downregulation of activated EGFR is inhibited (and EGFR signaling is sustained), which could be due to Alix blocking the SETA-endophilin complex from promoting rapid internalization of receptors and/or could be due to Alix facilitating deubiquitylation of Cbl substrates. Note that the non-phosphorylated form of Alix constitutively associates with EGFR (represented by a double-headed arrow) regardless of the activation state of the receptor, although this association appears to occur indirectly. (B) Phosphorylation of Alix by Src prevents Alix from binding SETA (Schmidt et al., 2005), thereby enabling association of Cbl with the SETA-endophilin complex as well as Cbl-mediated ubiquitylation, which promotes downregulation of receptors. e, endophilin; Ub, ubiquitin.