Sjögren syndrome/scleroderma autoantigen 1 is a direct Tankyrase binding partner in cancer cells

Abstract

Sjögren syndrome/scleroderma autoantigen 1 (SSSCA1) was first described as an autoantigen 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 Cterminal 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.

Arpin regulates migration persistence by interacting with both tankyrases and the Arp2/3 complex

“…Together these experiments indicate that Arpin is a direct TNKS partner, which is unlikely to be subjected to PARylation-mediated degradation. The situation of Arpin contrasts with the majority of TNKS binding partners, but is similar to several previously described TNKS binding partners that are not PARylated, such as Mcl-1L, GDP Mannose 4,6 Dehydratase, CD2AP, SSSCA1 (Bae, Donigian, and Hsueh 2003;Bisht et al 2012;Kuusela et al 2016;Perdreau-Dahl et al 2020).…”

Development of a 1,2,4-Triazole-Based Lead Tankyrase Inhibitor: Part II

“… 1 − 4 Independent of their catalytic activity, TNKS1/2 also provides scaffolding functions that are important in the formation of protein complexes. 5 − 8 TNKS1/2 PARylate a plethora of target proteins including peroxisome proliferator-activated receptor-gamma coactivator 1 α (PGC-1α), telomeric repeat binding factor 1 (TRF1), phosphatase and tensin homologue (PTEN), AMP-activated protein kinase (AMPK), SRY-box transcription factor 9 (SOX9), and SH3 domain binding protein 2 (SH3BP2). 3 , 9 − 15 In particular, TNKS1/2 regulate the turnover of AXIN1, AXIN2 (AXIN1/2) and of angiomotin (AMOT) proteins at the crossroad of the elementary wingless-type mammary tumor virus integration site (WNT)/β-catenin and Hippo signaling pathways, respectively.…”

“…Tankyrase 1 and tankyrase 2 (TNKS1/2) are members of the poly­(ADP-ribose) polymerase (PARP) family of enzymes that regulate the turnover of specific target proteins through covalently linking the cellular redox metabolite NAD + to target proteins in a process called poly-ADP-ribosylation (PARylation). The PAR chain produced in this post-translational modification is subsequently recognized by the E3 ubiquitin ligase ring finger protein 146 (RNF146) leading to poly-ubiquitination of the PARylated target proteins followed by proteasomal degradation. − Independent of their catalytic activity, TNKS1/2 also provides scaffolding functions that are important in the formation of protein complexes. − TNKS1/2 PARylate a plethora of target proteins including peroxisome proliferator-activated receptor-gamma coactivator 1 α (PGC-1α), telomeric repeat binding factor 1 (TRF1), phosphatase and tensin homologue (PTEN), AMP-activated protein kinase (AMPK), SRY-box transcription factor 9 (SOX9), and SH3 domain binding protein 2 (SH3BP2). ,− In particular, TNKS1/2 regulate the turnover of AXIN1, AXIN2 (AXIN1/2) and of angiomotin (AMOT) proteins at the crossroad of the elementary wingless-type mammary tumor virus integration site (WNT)/β-catenin and Hippo signaling pathways, respectively. ,,, Hence, controlling the catalytic activity of tankyrase by pharmacological intervention provides an attractive tool for reducing WNT/β-catenin and Hippo signaling. , …”

Arpin Regulates Migration Persistence by Interacting with Both Tankyrases and the Arp2/3 Complex

“…Together, these experiments indicated that Arpin is a direct TNKS partner that is unlikely to be subjected to PARylation-mediated degradation. This is different from the majority of TNKS-binding partners; however, several other TNKS-interacting partners that are not PARylated have been previously identified, such as Mcl-1L, GDP Mannose 4,6 Dehydratase, CD2AP, and SSSCA1 [22][23][24][25].…”