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In contrast to humans, parasite E3 ligases have not been extensively studied. Here, we characterize a unique\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    E3 ligase that has both RING and HECT\u2010like features with zinc\u2010coordinating domains.\n                    <jats:italic>Plasmodium<\/jats:italic>\n                    encodes a single RING\u2010between\u2010RING (RBR) E3 ligase that has evolutionarily diverged from human and other intracellular parasites. This RBR\u2010E3 ligase is expressed throughout the erythrocytic phase of the\n                    <jats:italic>P. falciparum<\/jats:italic>\n                    lifecycle. Immunoprecipitation experiments showed that\n                    <jats:italic>Pf<\/jats:italic>\n                    RBR\u2010E3 ligase catalyzes K6, K11, K48, and K63 mediated polyubiquitination, hinting towards its probable biological roles (DNA repair, proteasomal degradation, mitochondrial quality control). We observed that\n                    <jats:italic>Pf<\/jats:italic>\n                    RBR\u2010E3 ligase interacts with UBCH5 and UBC13 family of E2\u2010conjugating enzymes. Through mutational analysis in\n                    <jats:italic>Pf<\/jats:italic>\n                    RBR\u2010E3 ligase, we identified residues in RING1 and RING2 domains that are critical for ubiquitination activity and its protein stability.\n                    <jats:italic>Pf<\/jats:italic>\n                    RBR\u2010E3 ligase exhibits differences in immunofluorescence profile upon exposure of the parasite to different genotoxic (MMS) and proteotoxic (MG132, FCCP and artemisinin derivative) stress. Our study opens up avenues for exploring the client substrates of\n                    <jats:italic>Pf<\/jats:italic>\n                    RBR\u2010E3 ligase and using this knowledge to design substrate\u2010specific protein degradation\u2010based alternative intervention strategies for malaria.\n                  <\/jats:p>","DOI":"10.1002\/prot.26813","type":"journal-article","created":{"date-parts":[[2025,3,12]],"date-time":"2025-03-12T01:19:06Z","timestamp":1741742346000},"page":"1436-1450","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Understanding the Role of\n                    <scp>RING<\/scp>\n                    \u2010Between\u2010\n                    <scp>RING E3<\/scp>\n                    Ligase of the Human Malaria Parasite"],"prefix":"10.1002","volume":"93","author":[{"given":"Varsha","family":"Kumari","sequence":"first","affiliation":[{"name":"Molecular Microbiology and Immunology Division CSIR Central Drug Research Institute (CSIR\u2010CDRI)  Lucknow India"},{"name":"Academy of Scientific and Innovative Research (AcSIR)  Ghaziabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seema","family":"Vidyarthi","sequence":"additional","affiliation":[{"name":"Molecular Microbiology and Immunology Division CSIR Central Drug Research Institute (CSIR\u2010CDRI)  Lucknow India"},{"name":"Academy of Scientific and Innovative Research (AcSIR)  Ghaziabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aradhya","family":"Tripathi","sequence":"additional","affiliation":[{"name":"Molecular Microbiology and Immunology Division CSIR Central Drug Research Institute (CSIR\u2010CDRI)  Lucknow India"},{"name":"Academy of Scientific and Innovative Research (AcSIR)  Ghaziabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nirupa","family":"Chaurasia","sequence":"additional","affiliation":[{"name":"Molecular Microbiology and Immunology Division CSIR Central Drug Research Institute (CSIR\u2010CDRI)  Lucknow India"},{"name":"Academy of Scientific and Innovative Research (AcSIR)  Ghaziabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niharika","family":"Rai","sequence":"additional","affiliation":[{"name":"Molecular Microbiology and Immunology Division CSIR Central Drug Research Institute (CSIR\u2010CDRI)  Lucknow India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richa","family":"Shukla","sequence":"additional","affiliation":[{"name":"Molecular Microbiology and Immunology Division CSIR Central Drug Research Institute (CSIR\u2010CDRI)  Lucknow India"},{"name":"Academy of Scientific and Innovative Research (AcSIR)  Ghaziabad India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shagufa Nisrat","family":"Noorie","sequence":"additional","affiliation":[{"name":"Molecular Microbiology and Immunology Division CSIR Central Drug Research Institute 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USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shakil","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Academy of Scientific and Innovative Research (AcSIR)  Ghaziabad India"},{"name":"Biochemistry and Structural Biology Division CSIR Central Drug Research Institute (CSIR\u2010CDRI)  Lucknow India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3786-2953","authenticated-orcid":false,"given":"Niti","family":"Kumar","sequence":"additional","affiliation":[{"name":"Molecular Microbiology and Immunology Division CSIR Central Drug Research Institute (CSIR\u2010CDRI)  Lucknow India"},{"name":"Academy of Scientific and Innovative Research (AcSIR)  Ghaziabad 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