{"gene":"TPPP2","run_date":"2026-04-28T21:42:59","timeline":{"discoveries":[{"year":2019,"finding":"TPPP2 protein localizes to elongating spermatids and mature sperm; in vitro inhibition of TPPP2 causes decreased sperm motility and ATP content; knockout mice show male subfertility with decreased sperm count and motility, associated with abnormal mitochondria lacking lamellar cristae, defective electron transfer chain, lower ATP levels, and decreased mitochondrial membrane potential in sperm. A potential TPPP2-interacting protein, eEF1b (eukaryotic translation elongation factor 1 beta), was identified by pulldown.","method":"Knockout mouse model, in vitro inhibition assay, co-immunoprecipitation/pulldown for interacting partner identification, subcellular localization by imaging, mitochondrial function assays (ATP measurement, membrane potential, electron microscopy)","journal":"Journal of cellular and molecular medicine","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype, multiple orthogonal methods (KO mouse, in vitro inhibition, organelle ultrastructure, biochemical assays, interactor identification), single lab but strong mechanistic follow-up","pmids":["30680919"],"is_preprint":false}],"current_model":"TPPP2 is required for normal sperm mitochondrial structure and function (cristae integrity, electron transport chain activity, and ATP production), localizes to elongating spermatids and mature sperm, and interacts with the translation elongation factor eEF1b; its loss causes oligoasthenozoospermia and male subfertility in mice."},"narrative":{"teleology":[{"year":2019,"claim":"The first functional characterization of TPPP2 established that it is a spermatid/sperm-expressed protein required for mitochondrial cristae formation, oxidative phosphorylation, and male fertility, resolving the previously unknown role of this tubulin polymerization promoting protein family member.","evidence":"TPPP2 knockout mouse with ultrastructural EM, mitochondrial membrane potential and ATP assays, in vitro inhibition, and pulldown identifying eEF1b as interactor","pmids":["30680919"],"confidence":"High","gaps":["Mechanism by which TPPP2 maintains mitochondrial cristae structure is unknown","Functional significance of the TPPP2–eEF1b interaction has not been determined","Whether TPPP2 acts on tubulin polymerization in spermatids, as implied by its family membership, has not been tested"]},{"year":null,"claim":"The molecular mechanism linking TPPP2 to mitochondrial cristae organization — whether direct or indirect — remains unresolved, and it is unknown whether TPPP2 has tubulin polymerization-promoting activity in germ cells.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural or biochemical reconstitution of TPPP2 activity","No independent replication of the knockout phenotype by another laboratory","Role of TPPP2 in human male infertility has not been investigated"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0]}],"complexes":[],"partners":["EEF1B2"],"other_free_text":[]},"mechanistic_narrative":"TPPP2 localizes to elongating spermatids and mature sperm, where it is essential for mitochondrial cristae integrity, electron transport chain function, and ATP production [PMID:30680919]. Knockout of TPPP2 in mice causes oligoasthenozoospermia and male subfertility, with sperm displaying abnormal mitochondria lacking lamellar cristae, reduced mitochondrial membrane potential, and decreased motility [PMID:30680919]. TPPP2 physically interacts with eEF1b (eukaryotic translation elongation factor 1 beta), though the functional significance of this interaction is not yet defined [PMID:30680919]."},"prefetch_data":{"uniprot":{"accession":"P59282","full_name":"Tubulin polymerization-promoting protein family member 2","aliases":["Protein p25-beta","TPPP/p18"],"length_aa":170,"mass_kda":18.5,"function":"Probable regulator of microtubule dynamics required for sperm motility (Probable). In contrast to other members of the family, has no microtubule bundling activity (PubMed:17105200)","subcellular_location":"Cytoplasm, cytosol; Cell projection, cilium, flagellum","url":"https://www.uniprot.org/uniprotkb/P59282/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TPPP2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TPPP2","total_profiled":1310},"omim":[{"mim_id":"616957","title":"TUBULIN POLYMERIZATION-PROMOTING PROTEIN FAMILY, MEMBER 3; TPPP3","url":"https://www.omim.org/entry/616957"},{"mim_id":"616956","title":"TUBULIN POLYMERIZATION-PROMOTING PROTEIN FAMILY, MEMBER 2; TPPP2","url":"https://www.omim.org/entry/616956"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Connecting piece","reliability":"Approved"},{"location":"Mid piece","reliability":"Approved"},{"location":"Principal piece","reliability":"Approved"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"testis","ntpm":251.0}],"url":"https://www.proteinatlas.org/search/TPPP2"},"hgnc":{"alias_symbol":["p25beta","p18","CT152"],"prev_symbol":["C14orf8"]},"alphafold":{"accession":"P59282","domains":[{"cath_id":"1.10.238.10","chopping":"1-107","consensus_level":"medium","plddt":87.1237,"start":1,"end":107},{"cath_id":"-","chopping":"109-149","consensus_level":"medium","plddt":83.701,"start":109,"end":149}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P59282","model_url":"https://alphafold.ebi.ac.uk/files/AF-P59282-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P59282-F1-predicted_aligned_error_v6.png","plddt_mean":85.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TPPP2","jax_strain_url":"https://www.jax.org/strain/search?query=TPPP2"},"sequence":{"accession":"P59282","fasta_url":"https://rest.uniprot.org/uniprotkb/P59282.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P59282/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P59282"}},"corpus_meta":[{"pmid":"8001816","id":"PMC_8001816","title":"Growth 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potential in sperm. A potential TPPP2-interacting protein, eEF1b (eukaryotic translation elongation factor 1 beta), was identified by pulldown.\",\n      \"method\": \"Knockout mouse model, in vitro inhibition assay, co-immunoprecipitation/pulldown for interacting partner identification, subcellular localization by imaging, mitochondrial function assays (ATP measurement, membrane potential, electron microscopy)\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype, multiple orthogonal methods (KO mouse, in vitro inhibition, organelle ultrastructure, biochemical assays, interactor identification), single lab but strong mechanistic follow-up\",\n      \"pmids\": [\"30680919\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TPPP2 is required for normal sperm mitochondrial structure and function (cristae integrity, electron transport chain activity, and ATP production), localizes to elongating spermatids and mature sperm, and interacts with the translation elongation factor eEF1b; its loss causes oligoasthenozoospermia and male subfertility in mice.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TPPP2 localizes to elongating spermatids and mature sperm, where it is essential for mitochondrial cristae integrity, electron transport chain function, and ATP production [PMID:30680919]. Knockout of TPPP2 in mice causes oligoasthenozoospermia and male subfertility, with sperm displaying abnormal mitochondria lacking lamellar cristae, reduced mitochondrial membrane potential, and decreased motility [PMID:30680919]. TPPP2 physically interacts with eEF1b (eukaryotic translation elongation factor 1 beta), though the functional significance of this interaction is not yet defined [PMID:30680919].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"The first functional characterization of TPPP2 established that it is a spermatid/sperm-expressed protein required for mitochondrial cristae formation, oxidative phosphorylation, and male fertility, resolving the previously unknown role of this tubulin polymerization promoting protein family member.\",\n      \"evidence\": \"TPPP2 knockout mouse with ultrastructural EM, mitochondrial membrane potential and ATP assays, in vitro inhibition, and pulldown identifying eEF1b as interactor\",\n      \"pmids\": [\"30680919\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which TPPP2 maintains mitochondrial cristae structure is unknown\",\n        \"Functional significance of the TPPP2–eEF1b interaction has not been determined\",\n        \"Whether TPPP2 acts on tubulin polymerization in spermatids, as implied by its family membership, has not been tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The molecular mechanism linking TPPP2 to mitochondrial cristae organization — whether direct or indirect — remains unresolved, and it is unknown whether TPPP2 has tubulin polymerization-promoting activity in germ cells.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural or biochemical reconstitution of TPPP2 activity\",\n        \"No independent replication of the knockout phenotype by another laboratory\",\n        \"Role of TPPP2 in human male infertility has not been investigated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"EEF1B2\"],\n    \"other_free_text\": []\n  }\n}\n```"}