Galvanization of Protein–Protein Interactions in a Dynamic Zinc Interactome

Abstract

The presence of Zn 2+ at protein-protein interfaces modulates complex function, stability, and introduces structural flexibility/complexity, chemical selectivity, and reversibility driven in a Zn 2+ -dependent manner. Recent studies have demonstrated that dynamically changing Zn 2+ affects numerous cellular processes, including protein-protein communication and protein complex assembly. How Zn 2+ -involved protein-protein interactions (ZPPIs) are formed and dissociate and how their stability and reactivity are driven in a zinc interactome remain poorly understood, mostly due to experimental obstacles. Here, we review recent research advances on the role of Zn 2+ in the formation of interprotein sites, their architecture, function, and stability. Moreover, we underline the importance of zinc networks in intersystemic communication and highlight bioinformatic and experimental challenges required for the identification and investigation of ZPPIs. Protein-Protein Interactome and the Role of Metal IonsA complete picture of protein-protein interactions (PPIs), also known as the protein-protein interactome (see Glossary), is crucial to understand cell molecular machinery at the system biology level [1-3]. Identification of protein molecular complexes requires the description of various aspects, such as composition, component affinity, and lifetime with series of spatial and physicochemical properties describing the interface between proteins. Considering both the affinity and lifetime of proteins to interact, obligate and nonobligate complexes can be found, where the latter are divided into permanent (mostly strong, irreversible) and transient (reversible, frequently with medium affinity). Transient complexes are characterized by smaller interfaces, frequently dependent on specific recognition patterns, where the limited surface meets the requirement of constituents to fold and exist independently without aggregation [4,5]. Their interfaces contain more residues of higher polarity stabilized by salt bridges and hydrogen bonds with more chain turns to gain flexibility [6][7][8]. The specificity of such interactions is also elevated by the utilization of the same interface for multiple interactions across evolution, where the local environment has been affecting the fast adaptation of mutations [9,10].

Structural basis and regulation of the reductive stress response

“…A Cys/His claw coordinates zinc at the protein interface Most proteins bind zinc through Cys or His residues (Kocy1a et al, 2021). In line with this notion, the zinc ions at the interface between FEM1B and FNIP1 are coordinated by one Cys (C186) and two His residues (H185 and H218) of FEM1B and three Cys residues (C580, C582, and C585) and one histidine (H587) of FNIP1 (Figures 2A and 2B).…”

Nucleobindin-2 consists of two structural components: The Zn2+-sensitive N-terminal half, consisting of nesfatin-1 and -2, and the Ca2+-sensitive C-terminal half, consisting of nesfatin-3

“…Nucb1, the paralogue of Nucb2, was previously characterized [48] as a Zn 2+ sensor with a high affinity for Zn 2+ with two Zn 2+ -binding sites ( K d = 32 nM). In contrast, the fitted complex formation constants for both Zn 2+ -binding sites of hsNucb2 are in the range of 10 -5 M and seem to be significantly lower than those of Nucb1 [48] , and hsNucb2 is characterized as a weak Zn 2+ -binding protein, as Zn 2+ is tightly buffered in the cell at concentrations in the low nanomolar to picomolar range [99] . Nucb2 amino acid sequences were determined to possess only one putative Zn 2+ binding site, which might implicate these protein differences [48] .…”

Protease and DNase Activities of a Very Stable High-Molecular-Mass Multiprotein Complex from Sea Cucumber Eupentacta fraudatrix

“…It was shown that the sea cucumber complex accumulates various elements, including those contained in very low concentrations in seawater. Some studies have shown that various metal ions can significantly affect the stability of complexes of very different nature, consisting of charged, hydrophobic and hydrophilic molecules [ 15 , 16 ], as well as proteins and nucleic acids [ 17 , 18 , 19 , 20 , 21 ]. The data indicate that metal-dependent interactions are formed, in addition to hydrogen bonds between the complex components [ 14 ].…”