Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency

Wortmann, Saskia B.; Ziętkiewicz, Szymon; Guerrero–Castillo, Sergio; Feichtinger, René G.; Wagner, Matias; Russell, Jacqui; Ellaway, Carolyn; Mróz, Dagmara; Wyszkowski, Hubert; Weis, Denisa; Hannibal, Iris; Stülpnagel, Celina von; Cabrera‐Orefice, Alfredo; Lichter‐Konecki, Uta; Gaesser, Jenna; Windreich, Randy M.; Myers, Kasiani C.; Lorsbach, Robert B.; Dale, Russell C.; Gersting, Søren W.; Prada, Carlos E.; Christodoulou, John; Wolf, Nicole I.; Venselaar, Hanka; Mayr, Johannes A.; Wevers, Ron A.

doi:10.1038/s41436-021-01194-x

Cited by 28 publications

(34 citation statements)

References 29 publications

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“…Importantly, the structures of CLPB allow us to map the disease related mutations (Capo-Chichi et al, 2015; Cupo and Shorter, 2020; Kanabus et al, 2015; Kiykim et al, 2016; Pronicka et al, 2017; Saunders et al, 2015; Wortmann et al, 2021; Wortmann et al, 2015) on the atomic model to understand their possible effect on the function of CLPB. Mutations associated with 3-MGA could be categorized into three types.…”

Section: Discussionmentioning

confidence: 99%

Structural and Functional Insights into the Action Mode of A Mitochondrial AAA+ Disaggregase CLPB

Liu

Dai

et al. 2022

Preprint

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The human AAA+ ATPase CLPB (aka, HSP78 and Skd3) is a protein disaggregase and functions to promote the solubilization of proteins in the mitochondrial intermembrane space. Unlike other AAA+ protein unfoldases or disaggregases, CLPB contains an ankyrin repeat containing domain (ANK) at its N-terminus. Mutations of CLPB are closely associated with a few human diseases, such as 3-methylglutaconic aciduria (3-MGA) and severe congenital neutropenia (SCN). The mechanism of CLPB functions as a disaggregase and the role of its unique ANK domain are currently unclear. Herein, we report a comprehensive structural characterization of human CLPB in both the apo- and substrate-bound states. Our data show that CLPB assembles into homo-tetradecamers in apo-state and dodecamers in the presence of a substrate, mediated by ANK domains via a "head-to-head" organization. Conserved pore-loops (PLs) on the ATPase domains form a spiral staircase to grasp and translocate the substrate in a step-size of two amino acid residues. We also show that the ANK domain is functionally essential, and more important, responsible for direct binding to various mitocondiral proteins in the inner membrane or intermembrane space. These results suggest that CLPB functions as a general disaggregase in mitochondria and highlight its potential as a target for the treatment of various mitochondria-related diseases.

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Section: Discussionmentioning

confidence: 99%

Structural and Functional Insights into the Action Mode of A Mitochondrial AAA+ Disaggregase CLPB

Liu

Dai

et al. 2022

Preprint

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“…Both MGCA7 and SCN are characterized by loss-of-function Skd3 mutations (Cupo and Shorter, 2020b; Kanabus et al, 2015; Kiykim et al, 2016; Pronicka et al, 2017; Saunders et al, 2015; Warren et al, 2022; Wortmann et al, 2016; Wortmann et al, 2021; Wortmann et al, 2015). Thus, in principle, both diseases could be treated by increasing Skd3 activity.…”

Section: Discussionmentioning

confidence: 99%

“…Due to low neutrophil counts, SCN patients are prone to life-threatening infections early in life and exhibit increased propensity for myelodysplastic syndromes or acute myeloid leukemia (Skokowa et al, 2017). By contrast, autosomal recessive or distinct biallelic mutations in Skd3 that impair disaggregase activity underlie 3-methylglutaconic aciduria type 7 (MGCA7) (Cupo and Shorter, 2020b; Kanabus et al, 2015; Kiykim et al, 2016; Pronicka et al, 2017; Saunders et al, 2015; Wortmann et al, 2016; Wortmann et al, 2021; Wortmann et al, 2015; Zhang et al, 2020). MGCA7 presents with elevated levels of 3-methylglutaconic acid, neurologic deterioration, and neutropenia (Wortmann et al, 2016; Wortmann et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

“…It is often assumed that the Skd3 structure and mechanism closely resemble that of bacterial ClpB and yeast Hsp104 (Capo-Chichi et al, 2015; Kanabus et al, 2015; Saunders et al, 2015). Yet, there have been few studies of Skd3 disaggregase activity (Cupo and Shorter, 2020b; Mroz et al, 2020; Warren et al, 2022; Wortmann et al, 2021). Unlike Hsp104 and ClpB, Skd3 does not require Hsp70 or Hsp40 to disaggregate disordered aggregates (Cupo and Shorter, 2020b).…”

Section: Introductionmentioning

confidence: 99%

“…Yet, there have been few studies of Skd3 disaggregase activity (Cupo and Shorter, 2020b;Mroz et al, 2020;Warren et al, 2022;Wortmann et al, 2021). Unlike Hsp104 and ClpB, Skd3 does not require Hsp70 or Hsp40 to disaggregate disordered aggregates (Cupo and Shorter, 2020b).…”

Section: Introductionmentioning

confidence: 99%

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Unique structural features govern the activity of a human mitochondrial AAA+ disaggregase, Skd3

Cupo

Rizo

Braun

et al. 2022

Preprint

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The AAA+ protein, Skd3 (human CLPB), solubilizes proteins in the mitochondrial intermembrane space, which is critical for human health. Skd3 variants with impaired protein-disaggregase activity cause severe congenital neutropenia (SCN) and 3-methylglutaconic aciduria type 7 (MGCA7). Yet how Skd3 disaggregates proteins remains poorly understood. Here, we report a high-resolution structure of a Skd3-substrate complex. Skd3 adopts a spiral hexameric arrangement that engages substrate via pore-loop interactions in the nucleotide-binding domain (NBD). Unexpectedly, substrate-bound Skd3 hexamers stack head-to-head via unique, adaptable ankyrin-repeat domain (ANK)-mediated interactions to form dodecamers. Deleting the ANK-linker region reduces dodecamerization and disaggregase activity. We elucidate apomorphic features of the Skd3 NBD and C-terminal domain that regulate disaggregase activity. We also define how Skd3 subunits collaborate to disaggregate proteins. Importantly, SCN-linked subunits sharply inhibit disaggregase activity, whereas MGCA7-linked subunits do not. Our findings illuminate Skd3 structure and mechanism, explain SCN and MGCA7 inheritance patterns, and suggest therapeutic strategies.

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Decoding Skd3 (Human CLPB): a Mitochondrial Protein Disaggregase Critical for Human Health

Cupo,

Shorter

2024

Israel Journal of Chemistry

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Protein folding is important for all life. Indeed, protein misfolding can result in catastrophic protein aggregation and toxicity. The pathways involved in reversing protein aggregation within human mitochondria had long been unknown. We recently discovered that Skd3 (human CLPB) is a potent mitochondrial protein disaggregase, which is regulated by the rhomboid protease PARL, and maintains the solubility of many important mitochondrial proteins. Skd3 variants underlie several debilitating human diseases, including 3‐methylglutaconic aciduria, severe congenital neutropenia, and premature ovarian insufficiency. Here, we describe advances in understanding Skd3 function, mechanism, and structure and place these discoveries in the context of physiology and disease.

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Neutropenia and intellectual disability are hallmarks of biallelic and de novo CLPB deficiency

Cited by 28 publications

References 29 publications

Structural and Functional Insights into the Action Mode of A Mitochondrial AAA+ Disaggregase CLPB

Structural and Functional Insights into the Action Mode of A Mitochondrial AAA+ Disaggregase CLPB

Unique structural features govern the activity of a human mitochondrial AAA+ disaggregase, Skd3

Decoding Skd3 (Human CLPB): a Mitochondrial Protein Disaggregase Critical for Human Health

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