Relationships of Fold, Function, and Sequence Similarities

In spite of the closely related functional roles of protein kinases and phosphatases in many biochemical pathways, a comparison of both enzyme classes exemplifies the variability of relationships among function, sequence, and fold. 

In principle, nature has decoupled protein function and protein fold. The most commonly known example for a fold conveying a broad variety of functions is the TIM barrel. First found in triosephosphate isomerase, the TIM barrel also occurs in proteins as diverse as aldose reductase, enolase, and adenosine deaminase (see, e.g., the review by Nagano et al. [104]). To date, the TIM barrel fold, as a generic scaffold, is associated with 15 different types of enzymatic functions. 

On the other hand, a particular protein function can be realized with different protein folds, and an example of this are protein phosphatases. Protein phosphatases feature two distinctively different catalytic mechanisms for hydrolytically cleaving phosphorylated amino acid residues. The active sites of serine/threonine protein phosphatases (PPs) contain two metal centers that directly activate a water molecule for nucleophilic attack of the phosphate ester bond. In contrast, protein tyrosine phosphatases (PTPs) [105] possess a Cys residue present in the active site loop containing the conserved PTP signature motif HCXXXXXRS. The Cys sidechain acts as the attacking nucleophile in the formation of a phosphocysteine intermediate, which is eventually hydrolyzed by a water molecule [106], The same catalytic mechanism is also shared by dual-specificity phosphatases (see below). 

A CavBase calculation found 14 pairs of matching pseudo-centers, resulting in the superposition of the two binding sites shown 

The pseudocenters are shown as spheres, and interaction types are indicated by colors (blue = donor, red = acceptor, yellow = donor/ acceptor, green = aliphatic), (a) and (b) were prepared with Insight II [144], and (c) was prepared with SYBYL [145]. 

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