Bioinformatic analysis of smoothelin family members supports tissue‐specific functions of unique C‐terminal calponin homology domains

Smoothelins are cytoskeletal proteins with a single C‐terminal calponin homology domain type 2 (CHD2). Little is known about the significance of variation in SMTN CHD2 domains, addressed here through analysis of public databases. A conserved 152 nt penultimate constitutive exon present in all SMTNs encodes helices II‐IV of CHD2 with high identity (nt/aa 63/65%). Variable CHD2s of SMTN (helices IV‐VI) are generated by alternative splicing of 165 nt exon E20. E20 and the CHD2 it encodes have high homology with the terminal constitutive exon of SMTNL1 (E8; nt/aa 72/75% identity). Unique to these CHD2 variants are a conserved extended nine amino acid C‐terminal tail containing KTKK ubiquitination motifs. When E20 of SMTN is skipped (SMTN E20−), constitutive terminal E21 codes for helices IV‐VI of CHD2. SMTN E21 has high identity with the terminal exon of SMTNL2 (E8; nt/aa 75/81% identity of aligned sequences) except for coding for a unique extended C‐terminus (24 nt; 8aa) conserved only in mammals. SMTN isoform expression is tissue‐specific: SMTNE20− and SMTNE20+ are highly expressed in SMC and non‐muscle cells, respectively, while SMTNL1 + 2 are highly expressed in skeletal muscle cells. Tissue‐specific expression of SMTN CHD2s with unique helices IV‐VI suggest tissue‐specific functions that require further study.