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Expansion of Divergent SEA Domains in Cell Surface Proteins and Nucleoporin 54

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Expansion of Divergent SEA Domains in Cell Surface Proteins and Nucleoporin 54 FOR THE RECORD Expansion of divergent SEA domains in cell surface proteins and nucleoporin 54 Jimin Pei1* and Nick V. Grishin1,2 1Howard Hughes Medical Institute 2Department of Biophysics and Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA Received 8 October 2016; Accepted 29 November 2016 DOI: 10.1002/pro.3096 Published online 15 December 2016 proteinscience.org Abstract: SEA (sea urchin sperm protein, enterokinase, agrin) domains, many of which possess autoproteolysis activity, have been found in a number of cell surface and secreted proteins. Despite high sequence divergence, SEA domains were also proposed to be present in dystroglycan based on a conserved autoproteolysis motif and receptor-type protein phosphatase IA-2 based on structural similarity. The presence of a SEA domain adjacent to the transmembrane segment appears to be a recurring theme in quite a number of type I transmembrane proteins on the cell surface, such as MUC1, dystroglycan, IA-2, and Notch receptors. By comparative sequence and structural analyses, we identified dystroglycan-like proteins with SEA domains in Capsaspora owc- zarzaki of the Filasterea group, one of the closest single-cell relatives of metazoans. We also detected novel and divergent SEA domains in a variety of cell surface proteins such as EpCAM, a/ e-sarcoglycan, PTPRR, collectrin/Tmem27, amnionless, CD34, KIAA0319, fibrocystin-like protein, and a number of cadherins. While these proteins are mostly from metazoans or their single cell rel- atives such as choanoflagellates and Filasterea, fibrocystin-like proteins with SEA domains were found in several other eukaryotic lineages including green algae, Alveolata, Euglenozoa, and Hap- tophyta, suggesting an ancient evolutionary origin. In addition, the intracellular protein Nucleoporin 54 (Nup54) acquired a divergent SEA domain in choanoflagellates and metazoans. Keywords: SEA domain; autoproteolysis; cell surface proteins; dystroglycan; cadherin; Nup54 Introduction urchin sperm protein 63 kDa, enterokinase (also The SEA domain was originally detected in a num- called enteropeptidase), agrin, perlecan, and several 1 ber of cell surface and secreted proteins such as sea membrane-associated mucins. It was proposed to have functions related to sugar moieties since it Additional Supporting Information may be found in the online often resides in heavily glycosylated multi-domain 1 version of this article. proteins. Both agrin and perlecan are large proteo- Conflict of Interest: None declared glycans responsible for interactions with numerous extracellular matrix and cell surface proteins.2 SEA Grant sponsor: National Institutes of Health; Grant number: GM094575; Grant sponsor: Welch Foundation; Grant number: domains are also present in two interphotoreceptor I-1505. matrix proteoglycans (IMPG1 and IMPG2). Muta- *Correspondence to: Jimin Pei, Howard Hughes Medical Insti- tions located in the SEA domains of IMPG1 and tute, University of Texas Southwestern Medical Center at Dallas, IMPG2 have been associated with genetic disorders Dallas, TX 75390. E-mail: [email protected] of vitelliform macular dystrophies3 and autosomal- Published by Wiley-Blackwell. VC 2016 The Protein Society PROTEIN SCIENCE 2017 VOL 26:617—630 617 recessive retinitis pigmentosa,4 respectively. SEA- limited sequence similarity to previously identified domain-containing mucins, such as MUC1 (Mucin-1) SEA domains such as those in MUC1 and agrin. and MUC16 (Mucin-16), have extensive O-linked Presence of an extracellular SEA domain in the glycosylation in their characteristic serine and membrane-proximal stem region appears to be a threonine-rich regions and have been linked to vari- recurring theme found in type I transmembrane pro- ous cancers.5,6 In addition to their roles in protection teins dystroglycan and MUC1 as well as some type and lubrication of the epithelial surfaces of the II transmembrane serine proteases such as enteroki- internal ducts, some of these mucins such as MUC1 nase, matriptase and matriptase-2. Such a theme is are involved in cell signaling that is regulated by also employed in another cell surface protein, the multiple events of proteolysis.7 The SEA-domain- receptor-type protein tyrosine phosphatase IA-2.24,25 containing enterokinase is a type II single-pass IA-2 is a type I transmembrane protein with a transmembrane protein (N-terminus located in cyto- ferredoxin-like extracellular domain adjacent to the sol). It initiates intestinal digestion by proteolytical- transmembrane segment. This ferredoxin-like 8 ly activating trypsin. Besides enterokinase, SEA domain was proposed to be a divergent SEA domain domains were found in a number of other type II based on 3-dimenional structural similarities and transmembrane serine proteases, including matrip- profile-based sequence similarity searches.24 More- 9 tase and matriptase-2. Matriptase, overexpressed over, Notch receptors possess an extracellular juxta- in numerous cancer cell lines, performs proteolysis membrane domain (the heterodimeric (HD) domain) on various cell surface proteins such as protease- of the ferredoxin fold with noticeable structural sim- activated receptor 2 (PAR-2) and the zymogen of the ilarity to mucin SEA domains and the IA-2 SEA 10 urokinase-type plasminogen activator. Matriptase- domains.26,27 Like signaling mucins,7 the HD 2 regulates iron homeostasis by proteolytic process- domains of Notch receptors are regulated by proteol- ing of hemojuvelin, the co-receptor of bone morpho- ysis events. The S1 furin cleavage site of the Notch 11 genetic protein. SEA domains were also observed HD domains is located in the same region as the in two adhesion-type G-protein coupled receptors autoproteolysis site of MUC1 SEA domain.26 Simi- 12,13 (GPR110 and GPR116) and the uromodulin like larities in structures and active site locations sug- 14 1 protein. gest that the Notch HD domain is evolutionarily The SEA domain in the type I single-pass trans- related to SEA domains. membrane protein MUC1 (C-terminus located in cyto- Divergent SEA domains in dystroglycan, IA-2, 15 sol) was found to undergo autoproteolysis, creating and Notch receptors suggest that SEA domain detec- two noncovalently bound a-subunit and b-subunit. tion can be a challenging task. Here, we rely on com- Structural studies of MUC1 SEA domain revealed parative sequence and structural analyses to find new that it adopts a ferredoxin-like fold, and the cleavage SEA domains and study their phylogenetic distribu- site is located in the middle of the b-hairpin of the sec- tions. New SEA domains are proposed to be present in 16 ond and third b-strands. The serine hydroxyl in the a number of cell surface proteins such as PTPRR, GS/// consensus motif (/: a hydrophobic residue) is EpCAM, collectrin/Tmem27, Amnionless, CD34, responsible for the autoproteolysis that occurs at the KIAA0319, fibrocystin-like protein, and several cad- glycine-serine peptide bond. SEA domains with this herins. SEA domains predate the last common motif also undergo proteolytic processing between the ancestor of metazoans, as they were discovered in conserved glycine and serine in other proteins such as dystroglycan-like proteins in Capsaspora owczarzaki MUC3 and MUC12,17 enterokinase,18 matriptase,19 (with conserved autoproteolysis motif) and fibrocystin- and the G-protein coupled receptor Ig-Hepta (the like proteins beyond Holozoa. The functional regula- mouse ortholog of the human protein GPR116),20 pre- tion of SEA domain proteolysis could affect a much sumably with the same autoproteolysis mechanism. broader range of cell surface proteins than previously However, this autoproteolysis motif is not conserved recognized. Interestingly, a new SEA domain was in all SEA domains. MUC16, for example, has multi- also found inside the cell in nucleoporin 54 (Nup54) ple SEA domains, and none of them possesses this in metazoans and choanoflagellates. motif.21 A few divergent copies of SEA domains have Results and Discussion been discovered by careful sequence and structure comparisons. One example is the SEA domains in Sequence similarity searches of canonical SEA the extracellular matrix receptor dystroglycan.22,23 domains Like MUC1, dystroglycan was processed into the Transitive PSI-BLAST28 searches (see Materials and ligand-binding a-subunit and the membrane-bound methods) starting from the SEA domain of MUC1 b-subunit. Secondary structure and tertiary struc- (NCBI GenBank accession: P15941.3, residues 1041- ture predictions coupled with the conservation of the 1143) detected more than ten thousand proteins con- autoproteolysis motif suggest that dystroglycan pos- taining SEA domains in the non-redundant protein sesses a divergent SEA domain,23 which exhibits database. They include all founding members of the 618 PROTEINSCIENCE.ORG Expansion of Divergent SEA Domains SEA domains1 as well as numerous other SEA- edge b-strands. These b-bulges create the /xx/ domain-containing proteins. We name this large set hydrophobic pattern (double underlined blue letters of SEA domains related to MUC1 SEA domain as in Fig. 1), with the two hydrophobic residues (/) “canonical SEA domains” to distinguish them from contributing to the core of the structure. MUC1 SEA the more divergent SEA domains that cannot be domain and Muc16 SEA domain have the /xx/x/ linked by PSI-BLAST, such as those in dystrogly- and /x/xx/ patterns in the second core b-strands can23 and receptor-type protein tyrosine phospha- respectively
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