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Mitogen-activated protein kinases (MAPKs) are involved in environmental signal sensing. They are thus expected to play key roles in the biology of Trypanosomatid parasites, which display complex life cycles and use extracellular cues to modulate cell differentiation. Despite their relevance, structural data of Trypanosomatid MAPKs is lacking. We have now determined the crystal structure of Leishmania...
To guide development of new drugs targeting methionyl-tRNA synthetase (MetRS) for treatment of human African trypanosomiasis, crystal structure determinations of Trypanosoma brucei MetRS in complex with its substrate methionine and its intermediate product methionyl-adenylate were followed by those of the enzyme in complex with high-affinity aminoquinolone inhibitors via soaking experiments. Drastic...
The CCAAT box is a frequent element of eukaryotic promoters, and its specific recognition by the conserved heterotrimeric CCAAT-binding complex (CBC) constitutes a key step in promoter organization and regulation of transcription. Here, we report the crystal structures of the CBC from Aspergillus nidulans in the absence and in complex with double-stranded DNA at 1.8 Å resolution. The histone-like...
Plasma membrane repair involves the coordinated effort of proteins and the inner phospholipid surface to mend the rupture and return the cell back to homeostasis. Here, we present the three-dimensional structure of a multiprotein complex that includes S100A10, annexin A2, and AHNAK, which along with dysferlin, functions in muscle and cardiac tissue repair. The 3.5 Å resolution X-ray structure shows...
How can pathogen proteins functionally hijack their hosts? In this issue of Structure, Aitio et al. reveal that the process involves coordinated intrinsic disorder in a short pathogen sequence that elegantly commandeers the tightly regulated cytoskeletal signaling in the host.
Proteins may undergo multiple conformational changes required for their function. One strategy used to estimate target-site positions in unknown structural conformations involves single-pair resonance energy transfer (RET) distance measurements. However, interpretation of inter-residue distances is difficult when applied to three-dimensional structural rearrangements, especially in homomeric systems...
In this issue of Structure, Roberts et al. discuss how cryo-electron microscopy single particle reconstructions of the microtubule-based motor dynein reveal dramatic nucleotide-dependent conformational changes. They provide insight into dynein force generation and hint at shared mechanisms with other AAA+ unfoldases.
Proteins of unknown function comprise a significant fraction of sequenced genomes. Defining the roles of these proteins is vital to understanding cellular processes. Here, we describe a method to determine a protein function based on the identification of its natural ligand(s) by the crystallographic screening of the binding of a metabolite library, followed by a focused search in the metabolic space...
In this issue of Structure, Shumilin and colleagues show the power of metabolite screening by means of X-ray crystallography to link an orphan protein domain with an orphan biochemical function. This result paves the way for large-scale functional annotation and sets new objectives for structural genomics.
The genomic RNA of Qβ virus is replicated by Qβ replicase, a template-dependent RNA polymerase complex. Qβ replicase has an intrinsic template-independent RNA 3′-adenylation activity, which is required for efficient viral RNA amplification in the host cells. However, the mechanism of the template-independent 3′-adenylation of RNAs by Qβ replicase has remained elusive. We determined the structure of...
Transforming growth factor (TGF)-β and BMP signaling is mediated by Smads 1–5 (R-Smads and Co-Smads) and inhibited by Smad7, a major hub of regulation of TGF-β and BMP receptors by negative feedback and antagonistic signals. The transcription coactivator YAP and the E3 ubiquitin ligases Smurf1/2 and Nedd4L target R-Smads for activation or degradation, respectively. Pairs of WW domain in these regulators...
Intrinsically disordered protein (IDP)-mediated interactions are often characterized by low affinity but high specificity. These traits are essential in signaling and regulation that require reversibility. Enterohaemorrhagic Escherichia coli (EHEC) exploit this situation by commandeering host cytoskeletal signaling to stimulate actin assembly beneath bound bacteria, generating “pedestals” that promote...
The NF-κB inducing kinase (NIK) regulates the non-canonical NF-κB pathway downstream of important clinical targets including BAFF, RANKL, and LTβ. Despite numerous genetic studies associating dysregulation of this pathway with autoimmune diseases and hematological cancers, detailed molecular characterization of this central signaling node has been lacking. We undertook a systematic cloning and expression...
WW domains are small modules that mediate protein/protein interactions. In this issue of Structure, Aragón and colleagues show that a WW domain of YAP can mediate complexes with either the canonical PY motif in an inhibitory Smad or engage in phosphorylation-dependent complexes with one of the activated Smads. The propensity of YAP WW to recognize a pSP motif is a surprising find with a number of...
Regulation of protein phosphatase 1 (PP1) is controlled by a diverse array of regulatory proteins. However, how these proteins direct PP1 specificity is not well understood. More than one-third of the nuclear pool of PP1 forms a holoenzyme with the nuclear inhibitor of PP1, NIPP1, to regulate chromatin remodeling, among other essential biological functions. Here, we show that the PP1-binding domain...
Ribonuclease (RNase) Z is involved in the maturation of the 3′ ends of transfer RNAs (tRNAs) in all three kingdoms of life. To prevent futile cycles of CCA addition and removal, eukaryotic RNase Z discriminates against mature tRNAs bearing a CCA motif, with the first cytosine residue (C74) being the key antideterminant. Here, we show that, remarkably, the B. subtilis enzyme does not discriminate against...
CDK9, the kinase of positive transcription elongation factor b (P-TEFb), stimulates transcription elongation by phosphorylating RNA polymerase II and transcription elongation factors. Using kinetic analysis of a human P-TEFb complex consisting of CDK9 and cyclin T, we show that the CDK9 C-terminal tail sequence is important for the catalytic mechanism and imposes an ordered binding of substrates and...
In this issue of Structure, de Leon-Boenig and colleagues bring to light several key characteristics of NF-κB inducing kinase (NIK), which is at the center of many pathological disorders, using an impressive body of structural and functional studies. Structures of NIK described here provide deep insights into the mechanism of NIK activity regulation and may facilitate the design of new generation...
Dynein ATPases are the largest known cytoskeletal motors and perform critical functions in cells: carrying cargo along microtubules in the cytoplasm and powering flagellar beating. Dyneins are members of the AAA+ superfamily of ring-shaped enzymes, but how they harness this architecture to produce movement is poorly understood. Here, we have used cryo-EM to determine 3D maps of native flagellar dynein-c...
Dynamin is a multidomain mechanochemical guanine triphosphatase that catalyzes membrane scission, most notably of clathrin-coated endocytic vesicles. A number of recent publications have provided structural and mechanistic insights into the formation of helical dynamin filaments assembled by dynamic interactions of multiple domains within dynamin. As a prerequisite for membrane scission, this oligomer...
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