Many major protein–protein interaction networks are maintained by ‘hub’ proteins with multiple binding partners, where interactions are often facilitated by intrinsically disordered protein regions that undergo post-translational modifications, such as phosphorylation. Phosphorylation can directly affect protein function and control recognition by proteins that ‘read’ the phosphorylation code, re-wiring the interactome. The eukaryotic 14-3-3 proteins recognizing multiple phosphoproteins nicely exemplify these concepts. Although recent studies established the biochemical and structural basis for the interaction of the 14-3-3 dimers with several phosphorylated clients, understanding their assembly with partners phosphorylated at multiple sites represents a challenge. Suboptimal sequence context around the phosphorylated residue may reduce binding affinity, resulting in quantitative differences for distinct phosphorylation sites, making hierarchy and priority in their binding rather uncertain. Recently, Stevers et al. [Biochemical Journal (2017) 474: 1273–1287] undertook a remarkable attempt to untangle the mechanism of 14-3-3 dimer binding to leucine-rich repeat kinase 2 (LRRK2) that contains multiple candidate 14-3-3-binding sites and is mutated in Parkinson's disease. By using the protein-peptide binding approach, the authors systematically analyzed affinities for a set of LRRK2 phosphopeptides, alone or in combination, to a 14-3-3 protein and determined crystal structures for 14-3-3 complexes with selected phosphopeptides. This study addresses a long-standing question in the 14-3-3 biology, unearthing a range of important details that are relevant for understanding binding mechanisms of other polyvalent proteins.
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Cover Image
Cover Image
Nanobodies reset the time of the bacterial LRRK2 cycle. A bacterial homologue of the Parkinson's disease (PD)-associated protein LRRK2 cycles between a dimeric and monomeric state concomitant with GTP binding and hydrolysis, and certain PD mutations disrupt this cycle by stabilizing the dimer. In this issue Leemans and co-workers (pp. 1203–1218) report the identification and characterization of a Nanobody that can allosterically modulate this GTPase cycle, thereby "resetting" the deregulating effect of PD mutations. The front image shows the structure of the bacterial LRRK2 that we previously solved in the background, with in the foreground the bacterial LRRK2 dimer/monomer cycle represented as a clock that is being reset by the Nanobody shown as the arrows of the clock hands. The image was created by Christian Galicia and provided by Wim Versées.
Reading the phosphorylation code: binding of the 14-3-3 protein to multivalent client phosphoproteins
Nikolai N. Sluchanko; Reading the phosphorylation code: binding of the 14-3-3 protein to multivalent client phosphoproteins. Biochem J 17 April 2020; 477 (7): 1219–1225. doi: https://doi.org/10.1042/BCJ20200084
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