Cancer associated missense mutations in BAP1 catalytic domain induce amyloidogenic aggregation: A new insight in enzymatic inactivation

Bhattacharya, Sushmita; Hanpude, Pranita; Maiti, Tushar Kanti

doi:10.1038/srep18462

Cited by 40 publications

(41 citation statements)

References 61 publications

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“…While the role of protein aggregation has been extensively studied in the context of proteostasis and neurodegenerative diseases, the observations reported in the Supporting Information Table S1 show that protein misfolding and aggregation are associated with several other types of human maladies. Consistent with these observations, evidence suggesting a role for aggregation in cancer is emerging . However, a potential role for protein aggregation in cardiovascular diseases needs to be investigated further.…”

Section: Resultsmentioning

confidence: 75%

Aggregation prone regions in human proteome: Insights from large‐scale data analyses

et al. 2017

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Protein aggregation leads to several burdensome human maladies, but a molecular level understanding of how human proteome has tackled the threat of aggregation is currently lacking. In this work, we survey the human proteome for incidence of aggregation prone regions (APRs), by using sequences of experimentally validated amyloid-fibril forming peptides and via computational predictions. While approximately 30 human proteins are currently known to be amyloidogenic, we found that 260 proteins (∼1% of human proteome) contain at least one experimentally validated amyloid-fibril forming segment. Computer predictions suggest that more than 80% of the human proteins contain at least one potential APR and approximately two-thirds (65%) contain two or more APRs; spanning 3-5% of their sequences. Sequence randomizations show that this apparently high incidence of APRs has been actually significantly reduced by unique amino acid composition and sequence patterning of human proteins. The human proteome has utilized a wide repertoire of sequence-structural optimization strategies, most of them already known, to minimize deleterious consequences due to the presence of APRs while simultaneously taking advantage of their order promoting properties. This survey also found that APRs tend to be located near the active and ligand binding sites in human proteins, but not near the post translational modification sites. The APRs in human proteins are also preferentially found at heterotypic interfaces rather than homotypic ones. Interestingly, this survey reveals that APRs play multiple, often opposing, roles in the human protein sequence-structure-function relationships. Insights gained from this work have several interesting implications towards novel drug discovery and development. Proteins 2017; 85:1099-1118. © 2017 Wiley Periodicals, Inc.

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Section: Resultsmentioning

confidence: 75%

Aggregation prone regions in human proteome: Insights from large‐scale data analyses

et al. 2017

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“…BAP1 (ubiquitin carboxyl-terminal hydrolase) is a deubiquitinase that acts as a tumor suppressor. Cancer-associated mutations within this gene were found to destabilize protein structure promoting β-amyloid aggregation in vitro, which is the pathological hallmark in Alzheimer’s disease 33 .…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

Keo

Mahfouz

Ingrassia

et al. 2019

Preprint

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25The molecular mechanisms underlying the caudal-to-rostral progression of Lewy body pathology in 26Parkinson's disease (PD) remain poorly understood. Here, we aimed to unravel transcriptomic signatures 27 across brain regions involved in Braak Lewy body stages in non-neurological controls and PD donors. 28Using human postmortem brain datasets of non-neurological adults from the Allen Human Brain Atlas, we 29 identified expression patterns related to PD progression, including genes found in PD genome-wide 30 associations studies: SNCA, ZNF184, BAP1, SH3GL2, ELOVL7, and SCARB2. We confirmed these 31 patterns in two datasets of non-neurological subjects (Genotype-Tissue Expression project and UK Brain 32 Expression Consortium) and found altered patterns in two datasets of PD patients. Additionally, co-33 expression analysis across vulnerable regions identified two modules associated with dopamine 34 synthesis, the motor and immune system, blood-oxygen transport, and contained microglial and 35 endothelial cell markers, respectively. Alterations in genes underlying these region-specific functions may 36 contribute to the selective regional vulnerability in PD brains. 37 38 3 Background 39 Parkinson's disease (PD) is characterized by a temporal caudal-rostral progression of Lewy body (LB) 40 pathology across a selected set of nuclei in the brain 1 . The distribution pattern of LB pathology is divided 41 into six Braak stages based on accumulation of the protein α-synucleinthe main component of LBs and 42 Lewy neuritesin the brainstem, limbic and neocortical regions 1 . Different hypotheses have been 43 brought forward to explain the evolving LB pathology across the brain, including: retrograde transport of 44 pathological α-synuclein via neuroanatomical networks, α-synuclein's prion-like behavior, and cell-or 45 region-autonomous factors 2,3 . Yet, the mechanisms underlying the selective vulnerability of brain regions 46 to LB pathology remains poorly understood, limiting the ability to diagnose and treat PD. 47 Multiplications of the SNCA gene encoding α-synuclein are relatively common in autosomal dominant PD 48and SNCA dosage has been linked to the severity of PD 4,5 . For other PD-associated variants, e.g. GBA 49and LRRK2, their role in progressive α-synuclein accumulation is less clear, although they have been 50 associated with mitochondrial (dys)function and/or protein degradation pathways [6][7][8] . On the other hand, 51 transcriptomic changes between PD and non-neurological controls of selected brain regions, e.g. the 52 substantia nigra, have identified several molecular mechanisms underlying PD pathology, including 53 synaptic vesicle endocytosis [9][10][11] . However, post-mortem human brain tissue of well-characterized PD 54 patients and controls is scarce, usually focuses on a select number of brain regions, and have a limited 55 coverage of patients with different Braak LB stages, resulting in low concordance of findings across 56 different studies 12 . 57Spatial gene expression patterns in the human ...

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“…In addition, inactivating mutations within the gene, including insertions, deletions, frameshift, nonsense and missense mutations, have all been reported 11. Studies have shown that the tumour suppressor effects of BAP1 depend on both deubiquitinating activity and nuclear localisation, typically lost by missense mutations and truncating mutations, respectively 10.…”

Section: Bap1 Gene Mutationsmentioning

confidence: 99%

“…Cancer-associated missense mutations in the UCH domain of BAP1 can lead to structural instability and β-amyloid aggregation in vitro. Aggregates of BAP1 accumulate in the cytoplasm and upregulate heat shock protein response, specifically with increased expression of Hsp90, which is known to be overexpressed in cancers 11. Furthermore, ubiquitin-conjugating enzyme UBE2O ubiquitinates the NLS of BAP1, resulting in its cytoplasmic sequestration.…”

Section: Bap1 Gene Mutationsmentioning

confidence: 99%

Gene of the month:BAP1

et al. 2016

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The BAP1 gene (BRCA1-associated protein 1) is a tumour suppressor gene that encodes a deubiquitinating enzyme (DUB), regulating key cellular pathways, including cell cycle, cellular differentiation, transcription and DNA damage response. Germline BAP1 mutations cause a novel cancer syndrome characterised by early onset of multiple atypical Spitz tumours and increased risk of uveal and cutaneous melanoma, mesothelioma, renal cell carcinoma and various other malignancies. Recognising the clinicopathological features of specific BAP1-deficient tumours is crucial for early screening/tumour detection, with significant impact on patient outcome.

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Cancer associated missense mutations in BAP1 catalytic domain induce amyloidogenic aggregation: A new insight in enzymatic inactivation

Cited by 40 publications

References 61 publications

Aggregation prone regions in human proteome: Insights from large‐scale data analyses

Aggregation prone regions in human proteome: Insights from large‐scale data analyses

Transcriptomic signatures of brain regional vulnerability to Parkinson’s disease

Gene of the month:BAP1

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