Structural basis for tetraspanin functions as revealed by the cryo-EM structure of uroplakin complexes at 6-Å resolution

Min, Guangwei; Wang, Huaibin; Sun, Tung‐Tien; Kong, Xiang‐Peng

doi:10.1083/jcb.200602086

Cited by 120 publications

(128 citation statements)

References 72 publications

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“…One is located in the LEL, and the second one is located in the TM2/ TM3 region, which is mainly composed of transmembrane regions (20). In addition, the analysis of urothelial plaques, hexagonally packed 16-nm uroplakin particles that cover the urothelial apical surface, by cryo-electron microscopy at 6 Å resolution revealed that the non-tetraspanin uroplakins were in contact with both the LEL and the transmembrane domains (most likely TM3 and/or TM4) of their tetraspanin partners (41).…”

Section: Discussionmentioning

confidence: 99%

The Ig Domain Protein CD9P-1 Down-regulates CD81 Ability to Support Plasmodium yoelii Infection

Charrin

Yalaoui

Bartosch

et al. 2009

Journal of Biological Chemistry

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Invasion of hepatocytes by Plasmodium sporozoites is a prerequisite for establishment of a malaria natural infection. The molecular mechanisms underlying sporozoite invasion are largely unknown. We have previously reported that CD81 is required on hepatocytes for infection by Plasmodium falciparum and Plasmodium yoelii sporozoites. CD81 belongs to the tetraspanin superfamily of transmembrane proteins. By interacting with each other and with other transmembrane proteins, tetraspanins may play a role in the lateral organization of membrane proteins. In this study, we investigated the role of the two major molecular partners of CD81 in hepatocytic cells, CD9P-1/EWI-F and EWI-2, two transmembrane proteins belonging to a novel subfamily of immunoglobulin proteins. We show that CD9P-1 silencing increases the host cell susceptibility to P. yoelii sporozoite infection, whereas EWI-2 knock-down has no effect. Conversely, overexpression of CD9P-1 but not EWI-2 partially inhibits infection. Using CD81 and CD9P-1 chimeric molecules, we demonstrate the role of transmembrane regions in CD81-CD9P-1 interactions. Importantly, a CD9P-1 chimera that no longer associates with CD81 does not affect infection. Based on these data, we conclude that CD9P-1 acts as a negative regulator of P. yoelii infection by interacting with CD81 and regulating its function.Malaria remains the most important parasitic human disease, responsible for nearly one million deaths each year (1). Plasmodium natural infection is initiated by the inoculation of sporozoites in the host by a female Anopheles mosquito.Within the first hours of infection the motile sporozoites reach the liver and invade hepatocytes, where they further differentiate into a replicative exo-erythrocytic form (EEF) 5 that will ultimately give rise to thousands of merozoites that initiate the pathogenic erythrocytic cycle. Plasmodium sporozoites invade hepatocytes actively by forming a membrane-bound compartment called the parasitophorous vacuole (PV), where the parasite resides for further intracellular development (2, 3). The nature of the molecular interactions mediating sporozoite invasion still remains elusive. Two well-characterized sporozoite surface proteins, the circumsporozoite protein and the thrombospondin-related adhesive protein, are known to interact with the liver heparan sulfate proteoglycans (HSPGs) (2, 3). HSPGs play a role in the initial sequestration of the sporozoites in the liver sinusoids (4, 5), and activate sporozoites for productive invasion, leading to proteolytic processing of the circumsporozoite protein (6). Two sporozoite proteins, P36 and P36p/ P52, were shown to play a major role during infection of hepatocytes (7-9). Both belong to a Plasmodium-specific family characterized by the presence of domains with six conserved cysteines, but their precise function during sporozoite invasion and/or maintenance of the PV early after invasion remains unknown.To date, the only host molecule clearly identified as being essential for sporozoite invasion is CD81. ...

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Section: Discussionmentioning

confidence: 99%

The Ig Domain Protein CD9P-1 Down-regulates CD81 Ability to Support Plasmodium yoelii Infection

Charrin

Yalaoui

Bartosch

et al. 2009

Journal of Biological Chemistry

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“…21 However, acting through this type of interaction was reported by only one group. The extracellular part of tetraspanins protrudes B5 nm from the cell membrane 55 which, together with much 'taller' (B20 nm) associated integrins, makes direct homophilic binding between CD151's on neighboring cells physically rather unlikely. Fluorescence Resonance Energy Transfer (FRET) analysis showed that CD151 and a3b1 integrin associated at the front and retracting rear of polarized migrating breast carcinoma cells in 2D and 3D matrices.…”

Section: Modulation Of Integrin-ligand Interactionsmentioning

confidence: 99%

CD151 in cancer progression and metastasis: a complex scenario

Sądej

Grudowska

Turczyk

et al. 2014

Laboratory Investigation

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Originally identified as a molecular organizer of interacting proteins into tetraspanin-enriched microdomains, the tetraspanin CD151 has now been shown to be involved in tumour progression. Increasing evidence emerging from in vitro, in vivo and clinical analyses implicates this tetraspanin in supporting growth of various types of tumours at different levels. It affects both cell autonomous behavior and communication with neighboring cells and the microenvironment. CD151 regulates post-adhesion events, that is, cell spreading, migration and invasion including subsequent intravasation and formation of metastasis. Present on both neoplastic and endothelial cells, CD151 is engaged in promotion of tumour neovascularization. The molecular mechanism of CD151 in cancer is based on its ability to organize distribution and function of interacting proteins, ie, laminin-binding integrins (a3b1, a6b1 and a6b4), receptors for growth factors (HGFR, EGFR and TGF-b1R) and matrix metalloproteinases (MMP-7, MMP-2 and MMP-9), which indicates its importance in disease development. Results of clinical analyses of CD151 expression in different types of cancer and a large number of in vivo models demonstrate its impact on tumour growth and invasion and implicate CD151 as a valuable diagnostic and prognostic marker as well as a potential target for anti-cancer therapy. INTRODUCTIONTumour cells progress through multiple orchestrated steps before metastatic lesions are established in distant organs. These steps include detachment from the primary tumour mass, invasion of the basement membrane, migration through the surrounding extracellular matrix (ECM) followed by intravasation and extravasation and, finally, colonization of a secondary anatomical site. Successful completion of this sequence requires intrinsic changes enabling phenotypic transformation of the cell and, at every step, its coordinated communication with the tumour's microenvironment. A complex network of intricate tumourstroma interactions involves integrin-dependent adhesion and cell migration on the ECM, ECM degradation by matrix metalloproteinases (MMPs), and activation of signalling pathways responsible for cell survival, proliferation and motility, triggered by growth factor receptors stimulated by the environment.

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“…crystallography is not an "all or nothing" approach, and structural information can be extracted even from poorly ordered 2D crystals. Electron crystallography has thus contributed structural information of many membrane proteins in the 10Å range, providing valuable information on the arrangement of the transmembrane α-helices in these proteins (e.g., [14][15][16]). …”

Section: A Game Of Numbers the Number Of Solved Structuresmentioning

confidence: 99%

Revival of electron crystallography

Hite

Raunser

Walz

2007

Current Opinion in Structural Biology

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SummarySince the structure determination of bacteriorhodopsin in 1990, much progress has been made in the further development and use of electron crystallography. In this review, we provide a concise overview of the new developments in electron crystallography concerning 2D crystallization, data collection and data processing. Based on electron crystallographic work on bacteriorhodopsin, the acetylcholine receptor and aquaporins, we highlight the unique advantages and future perspectives of electron crystallography for the structural study of membrane proteins. These advantages include the visualization of membrane proteins in their native environment without detergent-induced artifacts, the trapping of different states in a reaction pathway by time-resolved experiments, the study of non-specific protein-lipid interactions and the characterization of the charge state of individual residues in membrane proteins. The structuresElectron crystallography began with Henderson and Unwin's groundbreaking work on the structure of purple membrane. Introducing glucose embedding as a new specimen preparation method and electron crystallographic data processing, these pioneers could produce a density map of bacteriorhodopsin (bR) at 7Å resolution [1,2]. The map resolved for the first time membrane-spanning α-helices and provided the first view of the structural organization of a membrane protein. After improvements in specimen preparation, data collection and data processing, Henderson and co-workers could finally present an atomic model of bR, the first structure solved by electron crystallography [3]. Since then, a higher resolution map of bR was obtained [4] and the structures of six more membrane proteins were solved by electron crystallography: plant light-harvesting complex 2 [5], aquaporin-1 [6,7], torpedo ray nicotinic acetylcholine receptor [8,9], sheep aquaporin-0 [10,11••], rat aquaporin-4 (solved using recombinant protein expressed in insect cells) [12••] and rat microsomal glutathione transferase 1 [13•]. A game of numbers The number of solved structuresSeven structures may appear a modest accomplishment compared to the many more membrane protein structures that have been determined by x-ray crystallography over the past few years. Considering, however, that less than two dozen groups are currently pursuing electron crystallography, compared to the hundreds of x-ray groups, the seven membrane protein structures determined by electron crystallography compare quite favorably to those determined by x-ray crystallography. More importantly, however, unlike x-ray crystallography, electronCorresponding author: Walz, Thomas (twalz@hms.harvard.edu) Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process...

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Structural basis for tetraspanin functions as revealed by the cryo-EM structure of uroplakin complexes at 6-Å resolution

Cited by 120 publications

References 72 publications

The Ig Domain Protein CD9P-1 Down-regulates CD81 Ability to Support Plasmodium yoelii Infection

The Ig Domain Protein CD9P-1 Down-regulates CD81 Ability to Support Plasmodium yoelii Infection

CD151 in cancer progression and metastasis: a complex scenario

Revival of electron crystallography

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