Abstract
Sjögren syndrome/scleroderma autoantigen 1 (SSSCA1) was first described as an auto-antigen over-expressed in Sjögren’s syndrome and in scleroderma patients. SSSCA1 has been linked to mitosis and centromere association and as a potential marker candidate in diverse solid cancers. Here we characterize SSSCA1 for the first time, to our knowledge, at the molecular, structural and subcellular level. We have determined the crystal structure of a zinc finger fold, a zinc ribbon domain type 2 (ZNRD2), at 2.3 Å resolution. We show that the C-terminal domain serves a dual function as it both behaves as the interaction site to Tankyrase 1 (TNKS1) and as a nuclear export signal. We identify TNKS1 as a direct binding partner of SSSCA1, map the binding site to TNKS1 ankyrin repeat cluster 2 (ARC2) and thus define a new binding sequence. We experimentally verify and map a new nuclear export signal sequence in SSSCA1.
Highlights
Sjögren syndrome/scleroderma autoantigen 1 (SSSCA1) was first described as an autoantigen over-expressed in Sjögren’s syndrome and in scleroderma patients
The human SSSCA1 gene is located on chromosome 11 (11q13.1) and encodes a small soluble protein of 21.5 kDa with a predicted N
The locus 11q13 where SSSCA1 is located has been shown to be rearranged and amplified in multiple human cancers by numerous genetic mechanisms including deletions, translocations, loss of heterozygosity and allelic amplifications[46,47,48,49,50]. This could be one of the reasons why SSSCA1 has been shown to be overexpressed in colorectal adenocarcinomas[10,11], identified as a target gene in breast cancer[12,13,14], and associated with disease progression and genomic instability in both metastatic oral squamous cell carcinoma[15] and pediatric metastatic neuroblastoma[16]
Summary
Sjögren syndrome/scleroderma autoantigen 1 (SSSCA1) was first described as an autoantigen over-expressed in Sjögren’s syndrome and in scleroderma patients. Wnt signaling pathway is a crucial pathway in animals implicated in a variety of cellular processes including proliferation, differentiation, motility, survival, and apoptosis Aberrant activation of this pathway often leads to cancer or other diseases, notably colorectal cancer for which more than 90% of the cases present an activating mutation[9]. SSSCA1 has been highlighted in numerous studies as a potential target gene and putative biomarker for breast cancer[12,13,14]. It has been associated with genomic instability at 11q and poor survival in both metastatic oral squamous cell carcinoma[15] and pediatric metastatic neuroblastoma[16]. SSSCA1 is indicated as a potential risk variant for type 2 diabetes[17]
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