Membrane Protein Complexes: Structure and Function by J. Robin Harris & Egbert J. Boekema

Author:J. Robin Harris & Egbert J. Boekema
Language: eng
Format: epub
Publisher: Springer Singapore, Singapore

8.2 SERCA Isoform Diversity and Tissue Distribution

Our detailed understanding of the structure and function of P-type ATPases is attributable to SERCA1a, the isoform present in and easily isolated from rabbit fast twitch skeletal muscle. It is presumed that the structure and function of SERCA1a is generally reflective of the entire family of P-type ATPases (Moller et al. 2010). Calcium pumps appear to be present in all living organisms from prokaryotes to mammals, though our understanding of prokaryotic calcium pumps remains rudimentary. Of the eukaryotic calcium pumps, three multigene families and nine members are currently known. There are three genes that encode SERCA pumps (SERCA1-3 or ATP2A1-3), four that encode plasma membrane calcium pumps (PMCA1-4 or ATP2B1-4), and two that encode secretory pathway calcium pumps (SPCA1-2 or ATPC2A1-2). These genes give rise to more than 40 different splice variants, which results in an impressive diversification of form, function, regulation, and physiological role (Brini et al. 2012).

In vertebrates, SERCA paralogues are encoded by a family of three genes – SERCA1, SERCA2, and SERCA3 – located on three different chromosomes. This family is highly conserved, with SERCA1 and SERCA2 being ~84% identical and SERCA3 being ~75% identical to either of the other paralogues. The isoform diversity of SERCA is amplified by alternative splicing of transcripts, which occur mainly in the C-terminus of the protein. These splicing variations give rise to thirteen currently known isoforms (SERCA1a-b, SERCA2a-d, and SERCA3a-f) (Wuytack et al. 2002; Dally et al. 2010). These SERCA isoforms exhibit both tissue and developmental specificity, reflecting their diversified functionality. The SERCA1 gene encodes two spliced variants primarily expressed in adult (SERCA1a; 994 residues) and fetal-neonatal (SERCA1b; 1001 residues) fast-twitch skeletal muscle. The SERCA1a and SERCA1b isoforms are functionally equivalent and differ by only seven additional residues at the C-terminus. While there is no specific structure or function associated with the extended C-terminus of SERCA1b, it is highly charged and may play a role in skeletal muscle development (Kosa et al. 2015). It is also interesting to consider that the C-terminus of the related sodium pump inserts into the membrane domain and modulates sodium affinity (Toustrup-Jensen et al. 2009). Thus, the short extension found in SERCA1b may modulate function during the developmental switch from fetal to adult skeletal muscle.

The SERCA2 gene is best known for encoding both the ubiquitous and cardiac-specific isoforms of SERCA (Vangheluwe et al. 2005). In all, four isoforms (SERCA2a-d) are generated by alternative splicing of the SERCA2 gene transcript. SERCA2b is a ubiquitous isoform expressed in all cell types, whereas SERCA2a is restricted to cardiac muscle, slow-twitch skeletal muscle and smooth muscle cells. In humans, SERCA2a encodes for a 997 amino acid protein and SERCA2b for a 1042 amino acid protein. These two isoforms differ by an unusual addition of 45 amino acids at the C-terminus, which gives SERCA2b an 11th transmembrane helix and places the C-terminus on the opposite side of the membrane in the lumen of the SR. The luminal tail and 11th transmembrane helix of SERCA2b imbue the highest calcium affinity amongst the SERCA isoforms (Gorski et al.

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