AAA ATPase systems: disaggregation, remodeling, and proteostasis leverage
🧪 lmctl-orchestrated review — written by an orchestrated team of AI agents, grounded in 2,286 papers from lmmol's literature graph. Citations link to their source on PubMed.
| Protein | Papers |
|---|---|
| Transitional endoplasmic reticulum ATPase | 90 |
| Spastin | 79 |
| Heat shock protein 104 | 56 |
| Mitochondrial inner membrane m-AAA protease component AFG3L2 | 45 |
| AAA family ATPase involved in ubiquitin-mediated protein degradation CDC48 | 37 |
| ATP-dependent zinc metalloprotease FtsH | 29 |
| Lon protease | 29 |
| Lon protease homolog, mitochondrial | 28 |
AAA ATPases are now best interpreted as molecular extractors: they couple repeated ATP hydrolysis cycles to forceful protein remodeling in many cellular compartments [1][2][3]. In modern literature, the family’s impact is less in “single-protein” function and more in how disaggregation, membrane dynamics, and organellar quality control coordinate through shared mechanical motifs [4][5][6].
1. Conserved cycle, divergent biology
The canonical cycle of substrate engagement, conformational grip, and reset is now linked to multiple disease-relevant outcomes, from proteostasis disorders to neurodegeneration [7][8][9]. In both cytosolic and organellar contexts, AAA ATPases are not passive chaperones: they often choose which aggregates persist, which are resolubilized, and which are triaged to downstream pathways [1][3][10].
2. Shifts in the recent literature
Recent years have moved AAA biology toward systems integration. Instead of single-factor narratives, studies connect ATPases to trafficking circuits, RNA-quality interfaces, and mitochondrial homeostasis checkpoints [11][12][5]. This is why newer reviews increasingly distinguish “housekeeping ATPases” from those with rewired physiological roles under stress, infection, and aging contexts [8][13].
3. Practical reading strategy in lmmol
For this family, the best graph neighborhoods are the ones that tie ATPase mechanics to outcome-linked biology: co-aggregation control, membrane remodeling, and disease loci overlap [2][6][12]. A ranking that blends this family-specific pathway context with co-citation is more predictive than raw degree, because high-connected hubs often reflect broad housekeeping burden rather than targeted mechanism [3][14][10].
References
- Glover J.R., Lindquist S.L. Hsp104, Hsp70, and Hsp40: a novel chaperone system that rescues previously aggregated proteins. Cell 1998. PubMed 1,089×
- Chernoff Y.O., Lindquist S.L., Ono B., Inge-Vechtomov S.G. et al. Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor [psi+]. Science 1995. PubMed 892×
- Parsell D.A., Kowal A.S., Singer M.A., Lindquist S.L. Protein disaggregation mediated by heat-shock protein Hsp104. Nature 1994. PubMed 718×
- Kaganovich D., Kopito R., Frydman J. Misfolded proteins partition between two distinct quality control compartments. Nature 2008. PubMed 770×
- Song Z., Chen H., Fiket M., Alexander C. et al. OPA1 processing controls mitochondrial fusion and is regulated by mRNA splicing, membrane potential, and Yme1L. J. Cell Biol 2007. PubMed 678×
- Casari G., De Fusco M., Ciarmatori S., Zeviani M. et al. Spastic paraplegia and OXPHOS impairment caused by mutations in paraplegin, a nuclear-encoded mitochondrial metalloprotease. Cell 1998. PubMed 643×
- Johnson J.O., Mandrioli J., Benatar M., Abramzon Y. et al. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 2010. PubMed 1,011×
- Hazan J., Fonknechten N., Mavel D., Paternotte C. et al. Spastin, a new AAA protein, is altered in the most frequent form of autosomal dominant spastic paraplegia. Nat. Genet 1999. PubMed 527×
- Babst M., Wendland B., Estepa E.J., Emr S.D. The Vps4p AAA ATPase regulates membrane association of a Vps protein complex required for normal endosome function. EMBO J 1998. PubMed 660×
- Sanchez Y., Lindquist S.L. HSP104 required for induced thermotolerance. Science 1990. PubMed 653×
- Nargund A.M., Pellegrino M.W., Fiorese C.J., Baker B.M. et al. Mitochondrial import efficiency of ATFS-1 regulates mitochondrial UPR activation. Science 2012. PubMed 863×
- Jarosch E., Taxis C., Volkwein C., Bordallo J. et al. Protein dislocation from the ER requires polyubiquitination and the AAA-ATPase Cdc48. Nat. Cell Biol 2002. PubMed 443×
- Hu H., Dai M., Yao J., Xiao B. et al. Overexpressing a NAM, ATAF, and CUC (NAC) transcription factor enhances drought resistance and salt tolerance in rice. Proc. Natl. Acad. Sci. U.S.A 2006. PubMed 853×
- Watts G.D.J., Wymer J., Kovach M.J., Mehta S.G. et al. Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nat. Genet 2004. PubMed 1,106×