Send Orders for Reprints to [email protected] Current Protein and Peptide Science, 2016, 17, 000-000 1 The Coronin Family and Human Disease Xiaolong Liua,*, Yunzhen Gaoa, Xiao Linb, Lin Lia,b, Xiao Hanc and Jingfeng Liua,b aThe United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, People’s Republic of China; bThe First Affiliated Hospital of Fujian Medical University, Fuzhou 350007, People’s Republic c of China; Biotechnology Research Institute, Chinese Academy of Agricultural Sciences, Beijing Please provide corresponding author(s) 100081, People’s Republic of China photograph size should be 4" x 4" inches Abstract: The Coronin family is one of the WD-repeat domain containing families that are diverse in both of their structures and functions. The first coronin was identified in the cytoskeleton composition of Dictyostelium discoideum, which was discovered to regulate the actin functions. So far, 723 coron- ins have been identified throughout the eukaryotic kingdom by bioinformatics analysis in 358 species. In mammals, 7 coronins have been identified to date, which are named through Coronin 1 to Coronin 7; all of these iso- forms contain two structurally conservational region: a 7-bladed β-propeller scaffold in N-terminal and a C-terminal vari- able coiled coil domain. Although some studies were showing that mammalian coronins have regulated the actin dynam- ics, recently many other functions such as calcium signaling regulation, cAMP signaling regulation, have been also re- ported beyond the actin modulation. Furthermore, many diseases have been found to be extensively associated with the abnormal expression of coronins, such as auto-immunity, bacterial and virus infection, neuronal behavior disorder and cancer. In this review, we would like to systematically discuss the recent progresses of mammalian coronins and associ- ated diseases, as well as possible underlying molecular mechanisms. Keywords: Coronin, human disease, cAMP signaling, cancer, WD repeats, actin associated protein 1. INTRODUCTION (1C); the type II class is including Coronin 4 (2A), Coronin 5 (2B) and Coronin 6; the type III class is only including The first coronin was identified through co-purifying Coronin 7 [4-6]. with F-actin at the crown-like structures on the dorsal surface of slime mold Dictyostelium discoideum by Hostos and col- According to the molecular signature, the coronins are leagues in 1991 [1, 2]. Afterwards, 723 coronins have been highly conserved WD-repeat domain containing proteins identified throughout the eukaryotic kingdom except in over roughly 800 million years of eukaryotic evolution [2, plants or distant protists by bioinformatics analysis in 358 9]. Coronins comprise three domains, a N-terminal of WD40 species [3]. repeats containing domain, a linker domain consisting of a C-terminal extension and an unique region at the C-terminal. In Dictyostelium discoideum, three coronin like proteins For some members of the family, there are a coiled coil have been identified, coronin or corA which is a short structure in the C-terminal. The coronins have seven WD40 coronin, Coronin7 (corB) and villidin which are belonging to repeats (seven bladed β propellers) assembled from five ca- the long coronins [4]. Unlike Dictyostelium discoideum, the nonical WD repeats and two noncanonical repeats in N- yeast only has a single coronin protein, termed as crn1 [5]. terminal domain (interact with actin or (and) membrane). But, there are ten coronin proteins in Danio retio (zebrafish) Following the WD motif is the C-terminal extension and [6]. unique region that differs in length and sequence among In mammals, there are 7 coronins were characterized to members of the family with poorly understood functions [7, date, and two synonymous names are used for the mammal- 10]. The coiled coil domain is the smallest functional region ian coronin family members. The mammalian coronin family of coronins and contribute to at least three different func- is including Coronin 1 (Coronin 1A), Coronin 2 (Coronin tional interactions: directly binding to actin, directly interact- 1B), Coronin 3 (Coronin 1C), Coronin 4 (Coronin 2A), ing with the Arp2/3 complex and the homo-oligomerization Coronin 5 (Coronin 2B), Coronin 6, and Coronin 7 [7, 8]. which is required for actin filaments bundling by coronin The mammalian coronins could be subdivided into three [11]. In mammals, all from Coronin 1 to Coronin 6 exhibit classes based on their sequence similarity; the type I class is the classical coronin structures, but Coronin 7, the longest including Coronin 1 (1A), Coronin 2 (1B), and Coronin 3 mammal coronin, lacks the coiled coil domain [12-14]. Coronins are expressed in distinct patterns across cell *Address correspondence to this author at the Xihong Road 312, Fuzhou types and tissues in mammalian, and the alternative splicing 350025, Fujian Province, P.R. China; Tel.: +86591-83705927; of the mRNA increases the differences of expression patterns E-mail: [email protected] among the vertebrate (Table 1). Coronin 1, having 2 iso- 1389-2037/16 $58.00+.00 © 2016 Bentham Science Publishers 2 Current Protein and Peptide Science, 2016, Vol. 17, No. ?? Stefano Costanzi Fig. (1). The structural domains and phylogenetic relationships of mammalian coronins. The phylogenetic tree (left) indicates that mammalian coronins could group into three classes. Seven human coronins have the same basic structure (right): an N-terminal extension (NE), a seven-bladed β-propeller, a C-terminal extension (CE) and an unique region (U). Type I and Type II coronins have a C-terminal coiled coil domain (CC), whereas the Type III coronin lacks this region but instead contains two tandem coronin repeats. Table 1. Summary of mammalian coronins. Subtype HGNC name Aliase Isoform: Protein Related Expression pattern Ref mRNA/protein length(aa) disease 1 Coronin 1A Coronin1; p57; 2/1 461 SCID; Hematopoietic cells [7, 11, IMD8; TACO; SLE; and tissues; Neuronal 34-45] CLABP; HCORO1; MS; Pathogenic tissues Clipin A infection Coronin 1B Coronin 2 2/1 489 Ubiquitously [12, 16] Coronin 1C Coronin 3; 3/2 527/474 Diffuse Gliomas; Ubiquitously [16, 60, HCRNN4 HCC; 62-64, Gastric Cancer; 66-70] Lung Cancer 2 Coronin 2A Coronin 4; IR10; 2/1 525 Inflammatory Testes; [7, 75] Clipin B; WDR2 Ovary; Uterus; Brain Coronin 2B Coronin 5; Clipin C 3/2 480/475 Ubiquitously with [14] high in brain Coronin 6 Coronin 6 1/1 472 CMS Ubiquitously with [7, 78, high in brain 79, 83] 3 Coronin 7 POD; CRN7 3/3 925/907/ 840 Obesity Ubiquitously [7, 13, 87] forms that encode the same protein, is mainly expressed in sues [12, 14]. Coronin 7, the vertebrate homolog of the hematopoietic cells and tissues with a low expression level in Caenorhabditis elegans gene POD, is expressed ubiquitously neuronal tissues [15]. Coronin 2 is ubiquitously expressed in but with low levels in heart, lung and muscle, and is alterna- most tissue with two mRNA isoforms that encode the same tively splicing into 3 isoforms [13, 18]. protein [16]. Coronin 3 the most ubiquitously expressed The functions of mammalian coronins are still not clearly coronin with 3 isoforms [17]. Coronin 4 is only expressed in unrevealed, especially in the coronins associated diseases. In testes, ovary, uterus and brain [12, 14]. Coronin 5 only pre- this review, we would like to discuss the recent key studies sents in the genome with little information in EST (expressed related to the coronins, and attempt to integrate the current sequence tag) database. Coronin 6, which has two isoforms, understanding of the functions of coronins into human dis- is enriched in brain with low expression levels in other tis- ease. The Coronin Family and Human Disease Current Protein and Peptide Science, 2016, Vol. 17, No. ?? 3 2. CORONIN 1 such an activity is involved in pathogen survival in macro- phages and / or T cell homeostasis [20, 29-34]. Coronin 1 (HGNC name: Coronin 1A, HGNC symbol: CORO 1A) is one of the best characterized mammalian 2.1. Coronin 1 Is Involved in the Diseases of Immune Sys- coronins and is highly expressed in cells of hematopoietic tem lineage and in neuronal tissues, where it localizes at the cell cortex [2, 19-22]. Originally, it was known as P57 associated The Coronin 1 is abundantly expressed in T cells, B cells, with phosphoinositol-specific phospholipase (PI-PL) C, and dendritic cells, macrophages, mast cells, neutrophils and was also studied as TACO (Tryptophan Aspartate containing neurons [21, 35], and it has been reported to be important for Coat protein) which is located around the mycobacteria- the functions of immune system. Mismatch function of containing phagosomes. With the better understanding of the Coronin 1 causes diverse of diseases in immune system in- mouse and human genomes, the P57 or TACO as well as cluding severe combined immunodeficiency (SCID) which is several homologous molecules were identified to belong to a characterized by profound block in T cells, partially with B member of protein family called coronins that were con- and NK cells defects [36]. Coronin 1 deficient patient served from yeast to human, and it was then referred as showed profound naïve T cell lymphopenia identified by coronin 1 [19] (Table 1). Structurally, Coronin 1 has three drastically reduced CD3+CD4+CD45RA+ and domains, a N-terminal (WD repeat-containing β-propeller), a CD3+CD8+CD45RA+ cells, but had intact thymus [37-40]. linker domain with coiled coil motif and an unique domain at This evidence indicates Coronin 1 is required to provide pro- the C-terminal [9]. The WD domain contains 7 bladed β- survival signals of CD4 as well as CD8 positive T cells. Fur- propeller which interacts with actin or (and) membrane. Bio- thermore, Coronin 1 is also an important modulator of auto- physical and structural analysis demonstrated that the C- immunity disease.