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SORCIN STRUCTURE AND ACTIVATION
Soluble resistance-related calcium binding protein (Sorcin) was named “resistance-related” since it was
[1]
found to be co-amplified with ABCB1 in multidrug (MD)-resistant cells . The gene coding for Sorcin (SRI)
is located in the chromosome region 7q21 and is about 21.9 kb-long. At least four alternative Sorcin isoforms
are transcribed, i.e., isoforms A (a transcript of 15 kb with eight exons and seven introns, translated into a
198-residues long, 22-kDa Sorcin), B, C and D, translated into shorter 19-kDa isoforms, where part of the
N-terminal domain and/or of the last aminoacids of the C-terminal domain are missing. Most literature
refers to isoform A, although a few studies deal about 19-kDa form of Sorcin. The pseudogene Sorcin-like
[2]
(SRIL) is in the chromosomal region 4q12 .

Sorcin is present in vertebrates, and more generally in metazoans. Its sequence is highly conserved among
species: protein sequences of mouse and human Sorcin show only eight differences, concentrated in the
second half of the protein, and six of them regard possibly phosphorylatable serine and threonine residues,
indicating that species-specific phosphorylation-dependent regulation of Sorcin may occur.

Usually calcium-binding proteins contain an even number of EF-hands, paired both structurally and
functionally. Sorcin belongs to the small penta-EF-hand (PEF) family, containing an odd (5) number of EF-
hands. Sorcin is a homodimer, although heterodimerization with another PEF protein, grancalcin, has been
observed . Sorcin monomers are formed by two domains, i.e., a rather short, flexible, glycine- and proline-
[3,4]
rich N-terminal domain and a C-terminal domain Sorcin calcium-binding domain (SCBD), globular and
composed by eight alpha-helices, which form five EF-hands (EF1-5) [Figure 1].

EF-hands couple through short β-sheets: EF1 pairs with EF2; EF3 pairs with EF4; the odd EF5 pairs with
another EF5, belonging to the other monomer, forming part of the dimeric interface. The dimer contains five
EF pairs and can be considered the structural unit of Sorcin. The long and rigid D- and G-helices connect
different EF-hands pairs, with the D-helix belonging to both EF2 and EF3, and the G-helix connecting EF4
and EF5. The SCBD can be divided in two subdomains: the EF1-3 subdomain (residues 33-134) is composed
by the three EF-hands that bind calcium with high affinity, while the EF4-5 subdomain (residues 135-198)
2+
mediates dimerization, contains many potential phosphorylation sites, but does not bind Ca with high
affinity. Calcium binding to EF hands determines the transition from a “closed” structure to an “open”
[5,6]
structure . Binding of calcium to EF3, the highest-affinity calcium-binding motif, EF2 and EF1 sites
activate Sorcin: Ca binding to EF3 alters the conformation of the loop containing Glu124, and this change
2+
is transmitted to EF2 via a movement of the long D-helix connecting EF3 with EF2. Overall, calcium binding
to the EF1-3 hands promotes a large conformational change in Sorcin structure, involving a movement of
the long D-helix and the opening of EF1, with the two subdomains moving away of 21° [Figure 1]. This
movement determines the exposure to solvent of hydrophobic residues of the D-helix, of the EF loop and
of the G-helix, with a consequent dramatic decrease of solubility, thus allowing Sorcin to translocate from
cytosol to membranes, and to bind and regulate a series of target proteins . The hydrophobic pocket can
[6-9]
accommodate in Ca -bound Sorcin a portion of the N-terminal domain displaying the consensus binding
2+
motif identified by phage display experiments [Figure 2].

THE ROLES OF SORCIN IN THE CELL: SORCIN LOCALIZATION, CELL CYCLE, AND FUNCTIONS

IN THE CELL
Sorcin is one of the most expressed human calcium binding proteins; it is expressed in most human tissues,
at high levels in bone, heart, brain, B- and T-lymphocytes, monocytes, kidney, breast and skin (sources:
MOPED, PaxDb and MaxQB databases) . In addition, Sorcin is overexpressed in many cancer types,
[2]
and especially in MD-resistant cells (see below). Cell localization of Sorcin is dynamic. During interphase
Sorcin is localized in the nucleus, in the cytosol, in the plasma membranes, at the endoplasmic reticulum