Solution Structure of the WNK1 Autoinhibitory Domain, a WNK-Specific PF2 Domain

Moon, Thomas M.; Corrêa, Fernando Morgan de Aguiar; Kinch, Lisa N.; Piala, Alexander T.; Gardner, Kevin H.; Goldsmith, Elizabeth J.

doi:10.1016/j.jmb.2013.01.031

Cited by 15 publications

(23 citation statements)

References 25 publications

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“…Comparison of the INI1 RPT1 structure to other known structures using the program dali reveals significant similarities to domains in two kinases involved in the regulation of osmotic stress, the CCT domain of oxidative stress responsive kinase 1 (OSR1) (Fig. C,D) and the autoinhibition domain of lysine‐deficient protein kinase 1 (WNK1) (Fig. C,D).…”

Section: Resultsmentioning

confidence: 99%

The structure of INI1/hSNF5 RPT1 and its interactions with the c‐MYC:MAX heterodimer provide insights into the interplay between MYC and the SWI/SNF chromatin remodeling complex

et al. 2018

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c-MYC and the SWI/SNF chromatin remodeling complex act as master regulators of transcription, and play a key role in human cancer. Although they are known to interact, the molecular details of their interaction are lacking. We have determined the structure of the RPT1 region of the INI1/hSNF5/BAF47/SMARCB1 subunit of the SWI/SNF complex that acts as a c-MYC-binding domain, and have localized the interaction regions on both INI1 and on the c-MYC:MAX heterodimer. c-MYC interacts with a highly conserved groove on INI1, while INI1 binds to the c-MYC helix-loop-helix region. The binding site overlaps with the c-MYC DNA-binding region, and we show that binding of INI1 and E-box DNA to c-MYC:MAX are mutually exclusive.

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Section: Resultsmentioning

confidence: 99%

The structure of INI1/hSNF5 RPT1 and its interactions with the c‐MYC:MAX heterodimer provide insights into the interplay between MYC and the SWI/SNF chromatin remodeling complex

et al. 2018

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“…The animal WNK1 AI domain binds Arg‐Phe‐Xaa‐Val (RFxV)‐containing peptides through the involvement of Asp‐531, Ile‐522, Phe‐524, and the formation of a putative RFxV‐binding groove between the β3–αA interface, which is coordinated by Phe‐524, Asp‐531, and Glu‐539 (Moon et al ., ) (Fig. a, RFxV‐binding cluster is within the red circle).…”

Section: Structure: Domains and Topologymentioning

confidence: 99%

“…The autoinhibitory domain of rat WNK1 comprises two linking a-helices (aA and aB) that lie adjacent to three b strands (b1, b2 and b3). A linker connects between b1 and b2, as well as between b2 and b3(Moon et al, 2013). Residues depicted in red, purple, or green color represent conserved amino acids that potentially form RFxV binding groove.…”

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confidence: 99%

Nudge‐nudge, WNK‐WNK (kinases), say no more?

et al. 2018

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Contents Summary 35 I Overview of animal and plant WNK kinases 35 II. Structure: domains and topology 36 III. Phylogeny-evolutionary relationships 41 IV. Plant WNK kinase distribution and regulation of WNK expression and activity 41 V. Functions of WNK family members in physiology and development 41 VI. Say no more? Still many questions to be answered 45 Acknowledgements 46 References 46 SUMMARY: WITH NO LYSINE (WNK) kinases are serine/threonine kinases uniquely characterized by an anomalous placement of a catalytic lysine, hence their moniker. In animals, WNK protein kinases play critical roles in protein trafficking of components that mediate renal ion transport processes and regulate osmoregulation of cell volume. In plants, the WNK kinase gene family is larger and more diverse. Recent studies revealed WNK kinase roles in orchestrating the trafficking of an ion channel, a lipid kinase complex in animals, and a heterotrimeric G protein signaling component in plants that is necessary for signal transduction. For this reason, new attention is geared toward investigating the mechanisms adopted by WNK kinases to nudge intracellular proteins to their destinations. In this review, the functions of WNK kinases in protein trafficking are derived from what we have learned from the model organism Arabidopsis thaliana. To place this new idea in context, we provide the predicted WNK kinase structures, their predicted expression patterns, a speculated evolutionary pathway, and the regulatory roles of plant WNKs in transport processes and other physiologies. We brazenly predict that the WNK kinases in both plants and animals will soon be recognized as a nexus for trafficking-based signal transduction.

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“…N-terminal WNK2 CCT-like domain (residues 454-549) bound to a WNK1-derived peptide with the sequence LTQVVHSAGRRFIVSPVPESRLR (residues 1247-1269) was solved by the Structural Genomics Consortium (Figure 2A,B) (Pinkas et al, 2017). WNK CCTL domains, discussed in more depth later, have an overall structure similar to CCT domains and the binding pocket residues that interact with the core motif are also highly conserved (Moon et al, 2013). In the case of this WNK2 CCTL1 structure, the peptide backbone makes an additional H-bond before being disrupted by a Pro residue in the peptide, and unlike the GRFQVT peptide, the Ser hydroxyl sidechain of the WNK1-derived peptide that follows the core motif no longer engages the backbone suggesting additional residues might bind through backbone H-bonds.…”

Section: Conserved C-terminal (Cct) Domainmentioning

confidence: 99%

“…found in WNKs share many of these conserved residues with CCT domains, and sequence alignments along with limited structural data indicate that CCTL2 domains also share most conserved binding pocket residues (Figure 2A) (Bartual et al, 2017;Moon et al, 2013;Pinkas et al, 2017;Pinkas et al, 2017). Based on structural information, it appears as though the core motif interactions are likely conserved but additional specificity determinants as dictated by the surrounding sequence of the motifs would likely be different owing to the decreased conservation outside the primary binding pocket in CCTL domains, and to a lesser extent between the OSR1 and SPAK CCT domains (Pinkas et al, 2017;Villa et al, 2007).…”

Section: Conserved C-terminal (Cct) Domainmentioning

confidence: 99%

CCT and CCT-Like Modular Protein Interaction Domains in WNK Signaling

Taylor

Cobb

2021

Mol Pharmacol

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The WNK (with-no lysine (K)) kinases and their downstream effector kinases, OSR1 (oxidative stress responsive 1) and SPAK (SPS/STE20-related proline-alanine rich kinase), have wellestablished functions in the maintenance of cell volume and ion homeostasis. Mutations in these kinases have been linked to an inherited form of hypertension, neurological defects, and other pathologies. A rapidly expanding body of evidence points to the involvement of WNKs in regulating multiple diverse cellular processes as well as the progression of some forms of cancer.How OSR1/SPAK contribute to these processes is well understood in some cases, but completely unknown in others. OSR1 and SPAK are targeted to both WNKs and substrates via their conserved C-terminal (CCT) protein interaction domains. Considerable effort has been put forth to understand the structure, function, and interaction specificity of the CCT domains in relation to WNK signaling, and multiple inhibitors of WNK signaling target these domains. The domains bind RFxV and RxFxV protein sequence motifs with the consensus sequence R-F-x-V/I or R-x-F-x-V/I, but residues outside the core motif also contribute to specificity. CCT interactions are required for OSR1 and SPAK activation and deactivation as well as cation-chloride cotransporter This article has not been copyedited and formatted. The final version may differ from this version.

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Solution Structure of the WNK1 Autoinhibitory Domain, a WNK-Specific PF2 Domain

Cited by 15 publications

References 25 publications

The structure of INI1/hSNF5 RPT1 and its interactions with the c‐MYC:MAX heterodimer provide insights into the interplay between MYC and the SWI/SNF chromatin remodeling complex

The structure of INI1/hSNF5 RPT1 and its interactions with the c‐MYC:MAX heterodimer provide insights into the interplay between MYC and the SWI/SNF chromatin remodeling complex

Nudge‐nudge, WNK‐WNK (kinases), say no more?

CCT and CCT-Like Modular Protein Interaction Domains in WNK Signaling

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