{"uniprot":"Q5JTY5","gene":"CBWD3","name":"COBW domain-containing protein 3","organism":"Homo sapiens (Human)","status":"dark","length":395,"sequence":"MLPAVGSVDEEEDPAEEDCPELVPIETTQSEEEEKSGLGAKIPVTIITGYLGAGKTTLLNYILTEQHSKRVAVILNESGEGSALEKSLAVSQGGELYEEWLELRNGCLCCSVKDNGLRAIENLMQKKGKFDDILLETTGLADPGAVASMFWVDAELGSDIYLDGIITIVDSKYGLKHLTEEKPDGLINEATRQVALADIILINKTDLVPEEDVKKLRTTIRSINGLGQILETQRSRVDLSNVLDLHAFDSLSGISLQKKLQHVPGTQPHLDQSIVTITFEVPGNAKEEHLNMFIQNLLWEKNVRNKDNHCMEVIRLKGLVSIKDKSQQVIVQGVHELYDLEETPVSWKDDTERTNRLVLIGRNLDKDILKQLFIATVTETEKQWTTHFKEDQVCT","function_summary":"A soluble human GTP-dependent metallochaperone that uses an NTPase switch coupled to a zinc-handling C-terminal module to activate zinc-requiring client proteins and ribosome-associated pathways. By transiently binding and transferring zinc in a GTP-driven cycle, it supports maturation of cytosolic and nuclear assemblies, consistent with pools in the cytosol and nucleoplasm. This regulated metallochaperone activity underpins broader developmental programs, including pathways essential for kidney formation.","plain_language":"CBWD3 has barely been studied. The model's best guess: A soluble human GTP-dependent metallochaperone that uses an NTPase switch coupled to a zinc-handling C-terminal module to activate zinc-requiring client proteins and ribosome-associated pathways. By transiently binding and transferring zinc in a GTP-driven cycle, it supports maturation of cytosolic and nuclear assemblies, consistent with pools in the cytosol and nucleoplasm.","uniprot_summary":"Involved in ribosome assembly.","go_terms":{"molecular_function":[{"id":"GO:0005515","label":"protein binding"}],"biological_process":[{"id":"GO:0001822","label":"kidney development"}],"cellular_component":[{"id":"GO:0005829","label":"cytosol"},{"id":"GO:0005654","label":"nucleoplasm"}]},"interpro":[{"id":"IPR027417","name":"P-loop containing nucleoside triphosphate hydrolase","type":"homologous_superfamily","start":40,"end":257},{"id":"IPR036627","name":"CobW-like, C-terminal domain superfamily","type":"homologous_superfamily","start":256,"end":375},{"id":"IPR003495","name":"CobW/HypB/UreG, nucleotide-binding domain","type":"domain","start":43,"end":229},{"id":"IPR011629","name":"Zinc chaperone CobW-like, C-terminal","type":"domain","start":274,"end":377},{"id":"IPR051316","name":"Zinc-regulated GTPase metalloprotein activator","type":"family","start":36,"end":376}],"reasoning":"I begin with the InterPro architecture. The N-terminal two-thirds of the protein are defined by IPR027417 (P-loop containing nucleoside triphosphate hydrolase homologous superfamily, residues 40–257) and the embedded IPR003495 (CobW/HypB/UreG nucleotide-binding domain, residues 43–229). This tandem establishes a classical P-loop NTPase core that binds and hydrolyzes GTP. The C-terminal third is specified by IPR036627 (CobW-like, C-terminal domain superfamily, residues 256–375) and IPR011629 (Zinc chaperone CobW-like, C-terminal, residues 274–377), which together form a metal-handling module characteristic of CobW-like GTPases. The entire polypeptide is encompassed by IPR051316 (Zinc-regulated GTPase metalloprotein activator family, residues 36–376), which functionally unifies the NTPase engine and the C-terminal metallochaperone appendage. The ordered layout—an N-terminal P-loop NTPase switch coupled to a C-terminal CobW-like metal-binding platform—creates a regulated GTP-dependent metallochaperone.\n\nThis architecture causes specific molecular functions. The P-loop NTPase core (IPR027417/IPR003495) confers GTP binding and hydrolysis, supporting GTPase activity and nucleotide-dependent conformational switching. The CobW-like C-terminus (IPR036627/IPR011629) provides a transient metal coordination site that loads Zn2+ and hands it to client proteins. Such a two-module system inherently relies on multivalent contacts with substrates and cofactors, which manifests as GO:0005515 protein binding. The coupling of a GTPase switch to a metallochaperone domain explains how the protein transiently binds zinc and uses GTP hydrolysis to drive unidirectional zinc transfer.\n\nFrom these molecular activities, the biological process follows. A GTP-driven zinc delivery system directly supports maturation of zinc-requiring enzymes and ribosomal components. By activating zinc-dependent pathways, the protein indirectly influences organogenesis programs that are sensitive to metalloprotein function; this aligns with involvement in GO:0001822 kidney development, where precise metal homeostasis and ribosome function are essential for nephrogenic signaling and biosynthesis.\n\nCellular location is inferred from the soluble, non-membranous architecture and the need to access both cytosolic maturation pathways and nuclear clients. The absence of transmembrane segments and the soluble domain composition point to a cytosolic pool, consistent with GO:0005829 cytosol. Dynamic participation in nuclear processes—such as ribosome assembly and zinc-dependent chromatin-associated enzymes—supports a nucleoplasmic fraction, consistent with GO:0005654 nucleoplasm. This dual soluble distribution matches the need to service cytosolic maturation and nuclear assembly pathways.\n\nMechanistically, the protein likely cycles between GTP- and GDP-bound states to regulate zinc handoff. In its GTP-bound form, the N-terminal switch domain and C-terminal CobW-like site cooperatively capture Zn2+. Hydrolysis of GTP triggers conformational changes that open the metal-binding pocket and promote transfer to acceptor proteins. This cycle predicts transient interactions with zinc-requiring client proteins and assembly factors. I hypothesize that it engages cytosolic ribosome assembly factors and zinc-requiring enzymes as primary partners, and in the nucleus it may contact nucleoplasmic assembly hubs. Through this regulated metallochaperone activity, it supports cytosolic and nuclear maturation pathways that ultimately influence organ development programs such as kidney formation.","category":"dark","control_evaluation":null,"validation_plan":null,"structure":{"source":"AlphaFold DB","pdb":"/structures/AF-Q5JTY5.pdb","alphafold":"https://alphafold.ebi.ac.uk/entry/Q5JTY5"},"links":{"uniprot":"https://www.uniprot.org/uniprotkb/Q5JTY5/entry","atlas":"/p/Q5JTY5"},"provenance":{"model":"BioReason-Pro (ESM3 esm3-sm-open-v1)","source_list":"Pharos Tdark","note":"AI prediction, not experimentally verified"}}