Review Article Molecular interactions shaping the tetraspanin web Sjoerd J. van Deventer*, Vera-Marie E. Dunlock* and Annemiek B. van Spriel Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, 6525GA Nijmegen, The Netherlands Correspondence: Annemiek B. van Spriel (annemiek.vanspriel@radboudumc.nl) To facilitate the myriad of different (signaling) processes that take place at the plasma membrane, cells depend on a high degree of membrane protein organization. Important mediators of this organization are tetraspanin proteins. Tetraspanins interact laterally among themselves and with partner proteins to control the spatial organization of mem- brane proteins in large networks called the tetraspanin web. The molecular interactions underlying the formation of the tetraspanin web were hitherto mainly described based on their resistance to different detergents, a classification which does not necessarily correl- ate with functionality in the living cell. To look at these interactions from a more physio- logical point of view, this review discusses tetraspanin interactions based on their function in the tetraspanin web: (1) intramolecular interactions supporting tetraspanin structure, (2) tetraspanin–tetraspanin interactions supporting web formation, (3) tetraspanin–partner interactions adding functional partners to the web and (4) cytosolic tetraspanin interactions regulating intracellular signaling. The recent publication of the first full-length tetraspanin crystal structure sheds new light on both the intra- and intermolecular tetraspanin interac- tions that shape the tetraspanin web. Furthermore, recent molecular dynamic modeling studies indicate that the binding strength between tetraspanins and between tetraspanins and their partners is the complex sum of both promiscuous and specific interactions. A deeper insight into this complex mixture of interactions is essential to our fundamental understanding of the tetraspanin web and its dynamics which constitute a basic building block of the cell surface. Introduction: spinning the tetraspanin web Tetraspanins are highly conserved integral membrane proteins involved in membrane organization and compartmentalization. This is achieved through lateral interactions among tetraspanins and between tetraspanins and their partner proteins, thereby forming tetraspanin-enriched microdomains (TEMs), also referred to as ‘the tetraspanin web’. The tetraspanin web creates a local environment containing a specific set of proteins in the plasma membrane which can facilitate or impede particular cellular processes [1]. Tetraspanins are small hydrophobic proteins that are ∼200–350 amino acids in length and protrude 3–5 nm from the cell surface [2,3]. They consist of four transmembrane (TM) regions, one small extracellular loop (EC1) and one large extracellular loop (EC2), one small cytoplasmic loop and two short cytoplasmic tails. Although there are many different four-TM-domain proteins present on the cell surface, not all of these proteins are considered part of the tetraspanin superfamily. For example, the MS4A protein family comprises four-TM-domain proteins (including CD20 and HTm4), which are not considered to be genuine tetraspanins [4]. Genuine tetraspanins are characterized by the pres- ence of a conserved CCG motif and two conserved cysteine residues located in the EC2 domain [5]. Tetraspanins have been shown to play a role in many vital cell biological processes, including adhe- sion, migration, fusion and signaling [6,7]. As a result of their involvement in these fundamental processes, tetraspanins have been implicated in the pathophysiology of numerous diseases, including HIV [8], hepatitis C [9], malaria [10], type 1 diabetes [11] and cancer [12]. The recent discovery that loss of a specific tetraspanin (CD37) leads to spontaneous development of B-cell lymphoma indicates *These authors contributed equally to this work. Version of Record published: 15 June 2017 Received: 17 January 2017 Revised: 14 March 2017 Accepted: 15 March 2017 © 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society 741 Biochemical Society Transactions (2017) 45 741–750 DOI: 10.1042/BST20160284 Downloaded from https://portlandpress.com/biochemsoctrans/article-pdf/45/3/741/723954/bst-2016-0284c.pdf by guest on 19 June 2020