Structure of the Tetraspanin Main Extracellular Domain

Seigneuret, Michel; Delaguillaumie, Alix; Lagaudrière-Gesbert, Cécile; Conjeaud, Hélène

doi:10.1074/jbc.m105557200

Cited by 187 publications

(82 citation statements)

References 42 publications

(43 reference statements)

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“…It spans the lipid bilayer four times, has cytoplasmically exposed amino and carboxy termini, and contains several distinctive cysteine motifs that are highly conserved within the family [7,8]. Like other tetraspanins, it also possesses a large hydrophilic loop (extracellular loop 2, EC2); this domain resides within the intradiskal space in rod photoreceptors, a location that corresponds to an extracellular exposure for cell-surface tetraspanins.…”

Section: Introductionmentioning

confidence: 98%

Predicted and Measured Disorder in Peripherin/rds, a Retinal Tetraspanin

Ritter

Arakawa²,

Goldberg³

2005

PPL

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Vertebrate photoreceptor outer segment (OS) morphogenesis requires peripherin/rds (P/rds). We have characterized this protein's C-terminus and present evidence that suggests it is intrinsically disordered. We propose that structural flexibility may underlie the multifunctionality proposed for this domain previously. The extremely short C-termini present in other tetraspanin family members suggest that intrinsic disorder may also play a role for those proteins.

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Section: Introductionmentioning

confidence: 98%

Predicted and Measured Disorder in Peripherin/rds, a Retinal Tetraspanin

Ritter

Arakawa²,

Goldberg³

2005

PPL

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“…The central role of the two disulfide bridges in stabilizing the EC2 structure was firmly established. In addition, most EC2s of tetraspanins are glycosylated in one or more potential N-glycosylation sites (11)(12)(13)(14).…”

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confidence: 99%

Cysteine Residues in the Large Extracellular Loop (EC2) Are Essential for the Function of the Stress-regulated Glycoprotein M6a

Fuchsová

Fernández

Alfonso

et al. 2009

Journal of Biological Chemistry

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Gpm6a was identified as a stress-responsive gene in the hippocampal formation. This gene is down-regulated in the hippocampus of both socially and physically stressed animals, and this effect can be reversed by antidepressant treatment. Previously we showed that the stress-regulated protein M6a is a key modulator for neurite outgrowth and filopodium/ spine formation. In the present work, mutational analysis was used to characterize the action of M6a at the molecular level. Glycoprotein M6a is a neuronally expressed member of the proteolipid protein (PLP/DM20) family (1) whose gene has been identified as a stress-responsive gene in the hippocampal formation. In several animal models of chronic stress, expression levels for M6a in hippocampal tissue were found to be diminished by chronic stress exposure and this effect was counteracted by treatment with antidepressants (2-3). Recently, an association of the M6A gene with the subgroup of schizophrenia patients with high levels of depression has been reported (4). These findings suggest that M6a plays a role in the stress-induced hippocampal alterations that are found in psychiatric disorders in general. M6a is prominently expressed in the central nervous system as early as embryonic day 10 and remains detectable in adulthood (5). Originally, it was identified as an antigen reacting with the monoclonal M6 antibody and its role as a modulator of neurite outgrowth was postulated (6). Lagenaur et al. (6) demonstrated that IgG or Fab fragments of M6 antibody interfere with the extension of neurites by cultured cerebellar neurons. A recent study by Zhao et al. (7) shows that M6a expressed in the murine neural retina also regulates neurite extension. The neurite outgrowth of M6a-overexpressing retinal cells was strikingly enhanced, although M6a did not affect differentiation and proliferation.Even though the precise biological function of M6a still remains unclear, there is a growing body of evidence indicating the importance of M6a in the processes of neural development such as neurite extension and differentiation. For example, a study by Mukobata et al. (8) reported that M6a expression enhances nerve growth factor-primed neurite extension in rat pheochromocytoma PC12 cells. They show that it also induces an increase in the intracellular Ca 2ϩ concentration of PC12 cells and that the anti-M6a antibody efficiently interferes with both nerve growth factor-triggered Ca 2ϩ influx and neurite extension (8). Next, inhibition of mouse M6a expression was found to lead to decreased differentiation of neurons derived from mouse embryonic stem cells (9). Furthermore, it has been demonstrated that M6a plays an important role in neurite/ filopodium outgrowth and synapse formation (10). This study shows that M6a overexpression induces neurite formation and increases filopodia density in hippocampal neurons. M6a knockdown with small interference RNA methodology showed that M6a low expressing neurons display decreased filopodia number and a lower density of synaptophysin clusters. Th...

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“…Thus the PA domain provides a protein-protein interaction domain to capture target transmembrane proteins as substrates. Although sequence alignments of the LEL of tetraspanins have revealed little primary sequence homology outside of small motifs necessary for disulfide bond formation and transmembrane regions, a common tertiary structure adopted by tetraspanins could serve as the site of interaction with the PA domain of GRAIL as suggested by recent modeling of the CD81 LEL region (32).…”

Section: Discussionmentioning

confidence: 99%

The Single Subunit Transmembrane E3 Ligase Gene Related to Anergy in Lymphocytes (GRAIL) Captures and Then Ubiquitinates Transmembrane Proteins across the Cell Membrane

Lineberry

Soares

et al. 2008

Journal of Biological Chemistry

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The ubiquitin E3 ligase gene related to anergy in lymphocytes (GRAIL) (Rnf128) is a type 1 transmembrane protein that induces T cell anergy through the ubiquitination activity of its cytosolic RING finger. GRAIL also contains an equally large luminal region consisting primarily of an uncharacterized protease-associated (PA) domain. Using two-hybrid technology to screen for proteins that bound the PA domain we identified CD151, a member of the tetraspanin family of membrane proteins. GRAIL bound to the luminal/extracellular portion of both CD151 and the related tetraspanin CD81 using its PA domain, which promoted ubiquitination of cytosolic lysine residues. GRAIL exhibited specificity for lysines only within the tetraspanin amino terminus even in the presence of other cytosolic lysine residues in the substrate. GRAIL-mediated ubiquitination promoted proteasomal degradation and cell surface downregulation of tetraspanins via Lys-48 linkages. As a result, the juxtaposition of PA and RING finger domains across a lipid bilayer facilitates the capture of transmembrane substrates for subsequent ubiquitination. These findings identify for the first time a single subunit E3 ligase containing a substrate-binding domain spatially restricted by a membrane from its E2 recruitment domain as well as an E3 ligase for members of the tetraspanin family.The ubiquitin proteasome pathway consists of a combination of proteins that determines with meticulous precision the post-translational fate of nearly every cellular protein. The sequential enzymes involved in conjugation of ubiquitin to a substrate, E1 2 activating enzymes, E2 transferases, and E3ligases, provide a mechanism of increasing stringency to ensure the serial transfer of ubiquitin to its intended target (1). The majority of substrate specificity is conferred by a wide array of protein interaction motifs on the E3 ligase that are separate from the domains responsible for recruitment of the ubiquitination machinery (2). After covalent attachment of ubiquitin, other classes of ubiquitin-binding proteins decipher this highly informative post-translational modification by binding, editing, or removing the attached ubiquitin molecules (3-5). E3 ligases are split into distinct families based on their E2 recruiting domains, including HECT, RING, and U box. RING finger proteins are the most numerous and can be further divided into multisubunit complexes (SCF and anaphase-promoting complex) or single subunit proteins with modular domains (Cbl and Mdm2). Multisubunit complexes partition function into individualized protein components with the substrate-binding region contained in the F box for the SCFs (6), whereas single subunit RING finger E3 ligases depend on substrate capture via protein-protein interaction domains particular to each (7). The regions critical for substrate binding among RING finger E3 ligases vary greatly, making prediction and identification of potential substrates difficult. In addition, the limited number of E3 ligases compared with the total number of prot...

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Structure of the Tetraspanin Main Extracellular Domain

Cited by 187 publications

References 42 publications

Predicted and Measured Disorder in Peripherin/rds, a Retinal Tetraspanin

Predicted and Measured Disorder in Peripherin/rds, a Retinal Tetraspanin

Cysteine Residues in the Large Extracellular Loop (EC2) Are Essential for the Function of the Stress-regulated Glycoprotein M6a

The Single Subunit Transmembrane E3 Ligase Gene Related to Anergy in Lymphocytes (GRAIL) Captures and Then Ubiquitinates Transmembrane Proteins across the Cell Membrane

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