Abstract
BRCA1-associated protein 1 (BAP1) is a nuclear localizing UCH, having tumor suppressor activity and is widely involved in many crucial cellular processes. BAP1 has garnered attention for its links with cancer, however, the molecular mechanism in the regulation of cancer by BAP1 has not been established. Amongst the four UCHs, only BAP1 and UCHL5 are able to hydrolyze small and large ubiquitin adducts but UCHL5 hydrolyzes only when it is present in the PA700 complex of the proteasome. The ability of BAP1 to cleave large ubiquitin derivatives is because of its relatively longer active-site crossover loop than other UCHs. The mechanism of ubiquitin recognition has not been studied for BAP1. The comparative enzymatic analysis of ubiquitin C-terminal hydrolase L1 (UCHL1), ubiquitin C-terminal hydrolase L3 (UCHL3), ubiquitin C-terminal hydrolase L5 (UCHL5N), and BAP1N has confirmed that enzymatically BAP1 is similar to UCHL5, which corroborates with the bioinformatics analysis done earlier. We have undertaken extensive mutational approaches to gain mechanistic insight into BAP1–ubiquitin interaction. Based on the homology-modeled BAP1 structure, we have identified a few BAP1 residues which possibly play a crucial role in ubiquitin interaction of which a few mutations have been identified in many cancers. Our comparative thermodynamic analysis reveals that BAP1–ubiquitin interaction is majorly driven by entropy factor which is unique amongst UCHs. Our study sheds light on BAP1 interaction with ubiquitin, which will be useful in understanding its enzymatic function.
Highlights
Breast cancer 1 (BRCA1)-associated protein 1 (BAP1) is a nuclear localizing deubiquitinating enzyme and a tumor suppressor protein, which was initially identified as an interactor of BRCA1 [1]
The kcat/Km value defines the catalytic efficiency of an enzyme and the estimated efficiency of the N-terminal catalytic domain of BAP1 (BAP1N) enzyme was 7.10 × 10−5 M−1s−1 that is comparable with ubiquitin C-terminal hydrolase L5 (UCHL5) and ubiquitin C-terminal hydrolase L1 (UCHL1)
We have investigated the enzymatic properties of BAP1N and compared it with other Ubiquitin C-terminal hydrolase (UCH) members
Summary
BRCA1-associated protein 1 (BAP1) is a nuclear localizing deubiquitinating enzyme and a tumor suppressor protein, which was initially identified as an interactor of BRCA1 [1]. The tumor suppressor function of BAP1 is dependent both on its nuclear localization and deubiquitinase activity [12]. We have reported that cancer-associated BAP1 catalytic N-terminal domain mutations abrogate its cellular functions due to the formation of β-amyloid aggregates [14]. During the last few years, BAP1 has gained a clinical interest as a critical tumor suppressor as its loss leads to induction of many cancers [15] including lung cancer, breast cancer, uveal melanoma, meningioma, pleural mesothelioma, and renal cell carcinoma [6,16,17,18,19,20,21,22,23,24,25,26,27,28]
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