Structural Basis for the Functional Diversity of Centrins: A Focus on Calcium Sensing Properties and Target Recognition

Abstract

Centrins are a family of small, EF hand-containing proteins that are found in all eukaryotes and are often complexed with centrosome-related structures. Since their discovery, centrins have attracted increasing interest due to their multiple, diverse cellular functions. Centrins are similar to calmodulin (CaM) in size, structure and domain organization, although in contrast to CaM, the majority of centrins possess at least one calcium (Ca2+) binding site that is non-functional, thus displaying large variance in Ca2+ sensing abilities that could support their functional versatility. In this review, we summarize current knowledge on centrins from both biophysical and structural perspectives with an emphasis on centrin-target interactions. In-depth analysis of the Ca2+ sensing properties of centrins and structures of centrins complexed with target proteins can provide useful insight into the mechanisms of the different functions of centrins and how these proteins contribute to the complexity of the Ca2+ signaling cascade. Moreover, it can help to better understand the functional redundancy of centrin isoforms and centrin-binding proteins.

Conformational Plasticity of Centrin 1 from Toxoplasma gondii in Binding to the Centrosomal Protein SFI1

“…All the free peptides have a random coil-type spectrum in solution ( Figure 5 , Figures S3 and S4 , black line). In contrast, TgCEN1 and its isolated lobes are well structured with both Ca 2+ and EGTA, and show spectral features typical of a protein with mainly α-helical structure (minima at 208 and 222 nm), as previously reported ( Figure 5 , Figures S3 and S4 ) [ 17 , 19 , 31 ].…”

“…Structural studies of centrin interactions have revealed that the basis for the target selectivity of centrins lies in their ability to interact with regions that have the propensity to form an α-helix and contain a hydrophobic triad, namely W 1 xxL 4 xxxL 8 (1–4–8 motif), which can be either in a forward (W 1 L 4 L 8 ) or reverse (L 8 L 4 W 1 ) orientation [ 6 , 12 , 18 ]. This sequence has been found in many centrin–target complex structures and validated by various biophysical techniques [ 6 , 12 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ].…”

“…There is increasing evidence that centrins are not restricted to centrosomes, but are found at several other sites in the cell, consistent with their emerging activities in several cellular processes, including DNA repair, mRNA nuclear export, and signal transduction [ 1 , 4 , 5 , 6 , 7 , 8 , 9 , 10 ]. The specificity of localization and functional diversity of centrins is likely achieved through interaction with multiple binding partners at centrosomes and spindle pole bodies (SPBs), or in other cellular compartments or organelles [ 4 , 5 , 6 , 7 , 8 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ].…”

Malaria parasite centrins assemble by Ca2+-inducible condensation

“…Centrins are conserved in all analyzed eukaryotes and implicated in a wide range of processes, which require their assembly ( 10 ). Our study in a highly divergent parasite reveals calcium-regulated phase separation as a new centrin assembly principle.…”

“…In mammalian cells, centrins are found inside the centrioles and are implicated in the function of centrosomes (8,9). Centrins contain four EF-hand (EFh) domains that can chelate calcium with high affinity, causing conformational changes (10,11). Calcium-dependent self-interaction of centrins has been documented in a range of eukaryotes including for human centrin 2, HsCen2 (10,(12)(13)(14)(15), although the nature of this interaction remains unclear.…”