Unique Structural Features of the Mitochondrial AAA+ Protease AFG3L2 Reveal the Molecular Basis for Activity in Health and Disease

Puchades, Cristina; Ding, Bojian; Song, Albert S.; Wiseman, R. Luke; Lander, Gabriel C.; Glynn, Steven E.

doi:10.1016/j.molcel.2019.06.016

Cited by 69 publications

(79 citation statements)

References 75 publications

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“…One of the notable features of this model is that not all ATPase subunits make contact with the substrate simultaneously; instead, at least one subunit is disengaged from the substrate upon ADP release (Figure 3c). This appears to be a common feature observed in most substrate-bound ATPase hexamer structures [131][132][133][134][138][139][140][141][142].…”

Section: How Are Substrate Interactions Coupled With Atp Hydrolysis?mentioning

confidence: 68%

“…To examine the native states, a cryo-EM structure of full-length yeast m-AAA protease with ATP bound at subnanometer resolution was acquired, which is fully compatible with crystal structures, confirming its broad structural resemblance to the bacterial FtsH [166]. To understand the translocation mechanisms of the FtsH-like proteases, cryo-EM structures of the substrate-bound yeast i-AAA Yme1 and human m-AAA AFG3L2 were solved at near-atomic resolution [132,133]. In both studies, the N-terminal transmembrane domains of all six subunits were genetically substituted with a soluble hexameric coiled coil to ensure both hexamerization and degradation activity in vitro.…”

Section: Ftsh-like Mitochondrial Proteasesmentioning

confidence: 90%

“…Substrate-contacting pore-1 loops of six RPT subunits are almost evenly distributed along the unfolded substrate polypeptide like a spiral staircase, with two adjacent pore-1 loops spanning two amino acid residues in the substrate, presumably corresponding to a one-step translocation driven by hydrolysis of a single ATP molecule [11]. This "two-residue spacing" of substrate-contacting pore-1 loops appears to be a key structural feature that is highly conserved among many AAA+ ATPases, including the 26S proteasome [11,118], Cdc48/p97 [76,131], FtsH-like AAA proteases [132,133], and Hsp104 disaggregase [134]. This suggests a conserved mechanism underlying the force generation by nonspecific, intercalated stacking interactions between the pore-1 loop's aromatic residues and the substrate sidechains.…”

Section: How Does a Substrate Interact With The Atpase Hexamer?mentioning

confidence: 99%

“…Because the majority of substrate-bound AAA+ ATPase structures were solved in only one conformation at high resolution as per their biochemical condition, the sequential "hand-over-hand" model of coordinated ATP hydrolysis around the ATPase ring is largely speculative and hypothetical [131][132][133]138,146]. In few studies where coexisting conformations were obtained, there were no intrinsic features that revealed the time sequence of the events along the pathway of chemical reactions [118,145,147].…”

Section: Is There Real Evidence For a Sequential Model Of Coordinatedmentioning

confidence: 99%

“…To understand the translocation mechanisms of the FtsH-like proteases, cryo-EM structures of the substrate-bound yeast i-AAA Yme1 and human m-AAA AFG3L2 were solved at near-atomic resolution [132,133]. In both studies, the N-terminal transmembrane domains of all six subunits were genetically substituted with a soluble hexameric coiled coil to ensure both hexamerization and degradation activity in vitro.…”

Section: Ftsh-like Mitochondrial Proteasesmentioning

confidence: 99%

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AAA+ ATPases in Protein Degradation: Structures, Functions and Mechanisms

Zhang

Mao

2020

Biomolecules

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Adenosine triphosphatases (ATPases) associated with a variety of cellular activities (AAA+), the hexameric ring-shaped motor complexes located in all ATP-driven proteolytic machines, are involved in many cellular processes. Powered by cycles of ATP binding and hydrolysis, conformational changes in AAA+ ATPases can generate mechanical work that unfolds a substrate protein inside the central axial channel of ATPase ring for degradation. Three-dimensional visualizations of several AAA+ ATPase complexes in the act of substrate processing for protein degradation have been resolved at the atomic level thanks to recent technical advances in cryogenic electron microscopy (cryo-EM). Here, we summarize the resulting advances in structural and biochemical studies of AAA+ proteases in the process of proteolysis reactions, with an emphasis on cryo-EM structural analyses of the 26S proteasome, Cdc48/p97 and FtsH-like mitochondrial proteases. These studies reveal three highly conserved patterns in the structure–function relationship of AAA+ ATPase hexamers that were observed in the human 26S proteasome, thus suggesting common dynamic models of mechanochemical coupling during force generation and substrate translocation.

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Section: How Are Substrate Interactions Coupled With Atp Hydrolysis?mentioning

confidence: 68%

Section: Ftsh-like Mitochondrial Proteasesmentioning

confidence: 90%

Section: How Does a Substrate Interact With The Atpase Hexamer?mentioning

confidence: 99%

Section: Is There Real Evidence For a Sequential Model Of Coordinatedmentioning

confidence: 99%

Section: Ftsh-like Mitochondrial Proteasesmentioning

confidence: 99%

See 3 more Smart Citations

AAA+ ATPases in Protein Degradation: Structures, Functions and Mechanisms

Zhang

Mao

2020

Biomolecules

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Expanding the clinical and genetic heterogeneity of SPAX5

Dosi

Galatolo

Rubegni

et al. 2020

Ann Clin Transl Neurol

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Mutations in the ATPase family 3-like gene (AFG3L2) have been linked to autosomal-dominant spinocerebellar ataxia type 28 and autosomal recessive spastic ataxia-neuropathy syndrome. Here, we describe the case of a child carrying bi-allelic mutations in AFG3L2 and presenting with ictal paroxysmal episodes associated with neuroimaging suggestive of basal ganglia involvement. Studies in skin fibroblasts showed a significant reduction of AFG3L2 expression. The relatively mild clinical presentation and the benign course, in spite of severe neuroimaging features, distinguish this case from data reported in the literature, and therefore expand the spectrum of neurological and neuroradiological features associated with AFG3L2 mutations.

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ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy

Caporali

Magri

Legati

et al. 2020

Annals of Neurology

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Objective Dominant optic atrophy (DOA) is the most common inherited optic neuropathy, with a prevalence of 1:12,000 to 1:25,000. OPA1 mutations are found in 70% of DOA patients, with a significant number remaining undiagnosed. Methods We screened 286 index cases presenting optic atrophy, negative for OPA1 mutations, by targeted next generation sequencing or whole exome sequencing. Pathogenicity and molecular mechanisms of the identified variants were studied in yeast and patient‐derived fibroblasts. Results Twelve cases (4%) were found to carry novel variants in AFG3L2, a gene that has been associated with autosomal dominant spinocerebellar ataxia 28 (SCA28). Half of cases were familial with a dominant inheritance, whereas the others were sporadic, including de novo mutations. Biallelic mutations were found in 3 probands with severe syndromic optic neuropathy, acting as recessive or phenotype‐modifier variants. All the DOA‐associated AFG3L2 mutations were clustered in the ATPase domain, whereas SCA28‐associated mutations mostly affect the proteolytic domain. The pathogenic role of DOA‐associated AFG3L2 mutations was confirmed in yeast, unraveling a mechanism distinct from that of SCA28‐associated AFG3L2 mutations. Patients' fibroblasts showed abnormal OPA1 processing, with accumulation of the fission‐inducing short forms leading to mitochondrial network fragmentation, not observed in SCA28 patients' cells. Interpretation This study demonstrates that mutations in AFG3L2 are a relevant cause of optic neuropathy, broadening the spectrum of clinical manifestations and genetic mechanisms associated with AFG3L2 mutations, and underscores the pivotal role of OPA1 and its processing in the pathogenesis of DOA. ANN NEUROL 2020 ANN NEUROL 2020;88:18–32

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Unique Structural Features of the Mitochondrial AAA+ Protease AFG3L2 Reveal the Molecular Basis for Activity in Health and Disease

Cited by 69 publications

References 75 publications

AAA+ ATPases in Protein Degradation: Structures, Functions and Mechanisms

AAA+ ATPases in Protein Degradation: Structures, Functions and Mechanisms

Expanding the clinical and genetic heterogeneity of SPAX5

ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy

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