Calcium-Binding Proteins with Disordered Structure and Their Role in Secretion, Storage, and Cellular Signaling

Abstract

Calcium is one of the most important second messengers and its intracellular signaling regulates many aspects of cell physiology. Calcium ions, like phosphate ions, are highly charged and thus are able to alter protein conformation upon binding; thereby they constitute key factors in signal transduction. One of the most common calcium-binding structural motifs is the EF-hand, a well-defined helix-loop-helix structural domain, present in many calcium-binding proteins (CBPs). Nonetheless, some CBPs contain non-canonical, disordered motifs, which usually bind calcium with high capacity and low affinity, and which represent a subset of proteins with specific functions, but these functions rarely involve signaling. When compared with phosphorylation-mediated signal transduction, the role of intrinsic disorder in calcium signaling is significantly less prominent and not direct. The list of known examples of intrinsically disordered CBPs is relatively short and the disorder in these examples seems to be linked to secretion and storage. Calcium-sensitive phosphatase calcineurin is an exception, but it represents an example of transient disorder, which is, nevertheless, vital to the functioning of this protein. The underlying reason for the different role of disordered proteins in the two main cellular signaling systems appears to be linked to the gradient of calcium concentration, present in all living cells.

The Influence of Calcium toward Order/Disorder Conformation of Repeat-in-Toxin (RTX) Structure of Family I.3 Lipase from Pseudomonas fluorescens AMS8

“…In contrast, in the absence of Ca 2+ ion, the RTX parallel β-roll motif repeat structure appeared to be disordered [27,28]. A previous study showed that the RTX parallel β-roll motif repeat structure became disordered and adequately unfolded in the absence of Ca 2+ ion [6][7][8][27][28][29]. In agreement with our previous laboratory work (CD spectra), in the absence of Ca 2+ ion (0 mM CaCl 2 ), the AMS8 lipase secondary structure, especially β-sheet content was decreased [14].…”

“…The RTX proteins show signs of an intrinsically disordered protein in the absence of Ca 2+ ion. Many experimental works have been conducted to prove the contribution of Ca 2+ ion [ 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. However, the study is scarce to further analyze the contribution of Ca 2+ ion toward the folding and stabilization of the RTX protein structure through in silico approaches.…”

“…Many factors affect the stability of the protein structure such as pH, temperature, various atomic/group interactions (hydrophobic, electrostatic, hydrogen bonding, van der Waals, and disulfide), and metal ion interaction (Zn 2+ , Ca 2+ ) [ 4 , 5 ]. The metal ion binding plays pivotal roles in protein structure, function, and stability, especially for the RTX protein structure [ 6 , 7 ]. Theoretically, the RTX protein structure is intrinsically disordered/unfolded in the absence of Ca 2+ ion [ 10 , 11 ].…”

Calcium binding to a disordered domain of a type III-secreted protein from a coral pathogen promotes secondary structure formation and catalytic activity

“…The high sequence similarity with NopE proteins suggests that a common molecular “post secretion host-sensing” conformational switch may exist in both beneficial and pathogenic T3SS-dependently secreted proteins. Ca 2+ -dependent disorder-to-order transitions are typical of numerous proteins secreted by type 1 secretion systems 33,34 . It is thus remarkable that the MIIA domain of the coral pathogen resides in a T3SS gene cluster, but exhibits a similar Ca 2+ -dependent transition from a disordered secretion-adapted state to a more compact structure with hydrophobic interactions.…”

Population demographic history and population structure for Pakistani Nili-Ravi breeding bulls based on SNP genotyping to identify genomic regions associated with male effects for milk yield and body weight

“…MAPK-interacting and spindle-stabilizing protein-like (Gene ID: S24_1645) is involved in regulating milk synthesis [91,[104][105][106]. EF-hand domain-containing 2 (Gene ID: S25_42968291) is one of the most common calcium-binding structural motifs, and a well-defined helix-loop-helix structural domain, present in many calcium-binding proteins, has been identified in milk [107][108][109][110]. Our results support these important insights into the synthesis of milk proteins and potential targets for the future improvement of milk quality.…”