LPX2 (systematic name YKL050C) is a large (922-residue, ~103 kDa), predominantly intrinsically disordered protein of the budding yeast Saccharomyces cerevisiae. It is a whole-genome-duplication paralog (ohnolog) of the eisosome protein EIS1, and its only recognizable sequence-family signature is shared EIS1/Eisosome1 ancestry (Pfam PF12757, InterPro IPR024527, PANTHER PTHR28298 "eisosome protein 1"); it carries no recognizable hydrolase or other catalytic domain. Despite this family placement, LPX2 was experimentally localized to the peroxisomal matrix in a systematic peroxisome-proteome study, and deletion of the gene produces the largest single change in the yeast lipidome under glucose growth (an accumulation of lyso-phosphatidylglycerol), which together with a reported lipase-like activity led to its naming as "Lipase of Peroxisomes 2." Its subcellular distribution (peroxisomal, nuclear and cytosolic) is dependent on the carbon source (oleate), its expression is induced by the transcription factor Azf1, and the protein is a reported substrate of the SCF(Cdc4) ubiquitin ligase. A direct, purified-protein enzymatic activity and physiological substrate for LPX2 have not been firmly established, so its molecular function remains provisional.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005777 peroxisome | IDA PMID:36164978 Systematic multi-level analysis of an organelle proteome rev... | ACCEPT | Summary: Direct experimental (IDA) localization of Ykl050c/Lpx2 to the peroxisome (peroxisomal matrix) in the Yifrach 2022 systematic peroxisome-proteome study. This is well supported and represents the most solidly established fact about the protein. Accept. Note that SGD reports the peroxisomal/nuclear/cytosolic distribution is oleate-dependent, so peroxisomal localization is condition-dependent rather than constitutive. Supporting Evidence: PMID:36164978 an additional newly identified peroxisomal lipase, hence we named Ykl050c, Lpx2 (Lipase of Peroxisomes 2) |
| GO:0003674 molecular_function | ND GO_REF:0000015 | KEEP AS NON CORE | Summary: Root molecular_function annotation with ND (No biological Data) evidence β a placeholder indicating that no experimentally determined molecular function has been curated for LPX2. This is an accurate reflection of the current state: although the gene is named as a putative lipase, no direct enzymatic activity has been established on the purified protein, and its only sequence-family signature (EIS1/Eisosome1) implies no hydrolase fold. Keep as the honest "unknown MF" placeholder; the specific molecular activity is a genuine knowledge gap (see knowledge_gaps). |
| GO:0008150 biological_process | ND GO_REF:0000015 | KEEP AS NON CORE | Summary: Root biological_process annotation with ND evidence β a placeholder indicating no experimentally curated biological process. A role in peroxisomal glycerophospholipid / lipid metabolism is suggested by the deletion lipidome phenotype (LPG accumulation), but this is a genetic association proposed in one study, not an established, curated process. Keep as the honest "unknown BP" placeholder; the in-vivo role is a knowledge gap. |
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Download this section (compressed HTML)Q: Does purified LPX2 have a measurable lipase/esterase activity, and if so on which lipid substrate class (triacylglycerol, phosphatidylglycerol, lyso-phosphatidylglycerol, other)?
Q: Is the single GXSXG motif (G875-S877-G879), which lies within a predicted disordered C-terminal region, a genuine catalytic serine, or is LPX2 catalytically inactive?
Q: How is LPX2 imported into the peroxisomal matrix given the absence of a canonical C-terminal PTS1, and what governs its oleate-dependent partitioning between peroxisome, nucleus and cytosol?
Q: Does LPX2 retain any EIS1-like eisosome-related function, or has it fully neofunctionalized after the whole-genome duplication?
Experiment: Express and purify recombinant LPX2 and assay hydrolytic activity against a defined lipid panel (tri/di/monoacylglycerol, major glycerophospholipids including phosphatidylglycerol and lyso-phosphatidylglycerol), with a catalytic-serine (S877A) mutant as a negative control.
Experiment: Construct lpx2Ξ, lpx1Ξ lpx2Ξ, and lpx1Ξ lpx2Ξ fsh3Ξ strains and phenotype for growth on oleate/fatty-acid carbon sources, beta-oxidation flux, quantitative lipidomics (confirming LPG accumulation), and peroxisomal membrane morphology by microscopy.
Experiment: Map LPX2's peroxisomal import determinants (test the non-canonical C terminus and any internal PTS) and image tagged LPX2 relative to eisosome markers (Pil1/Lsp1) to test the eisosome-family inference directly.
What is not known β curated, literature-grounded statements of the open unknowns (the inverse of core functions).
Gap: The direct molecular function and physiological substrate of LPX2 are unknown. The "peroxisomal lipase" designation rests on gene-deletion lipidomics plus a literature attribution of lipase activity (Ploier et al. 2013) that is actually a NEGATIVE direct result: that study tested Ykl050cp in vivo and it did not exhibit lipolytic activity (only Lpx1p and Ayr1p were confirmed as lipases); no purified-protein enzymatic assay or substrate specificity has been established, and the protein has no recognizable hydrolase domain.
OPEN BIOLOGYCURATION MF_DARK
What is known: Firmly known: LPX2/YKL050C is experimentally localized to the peroxisomal matrix (IDA, PMID:36164978); its deletion produces the largest single glucose-medium change in the yeast lipidome (lyso-phosphatidylglycerol accumulation); its expression is Azf1-induced; it is an SCF(Cdc4) substrate; and it is the whole-genome-duplication paralog of the eisosome protein EIS1, which is also its sole sequence-family signature.
Significance: LPX2 is a conserved (pan-Saccharomycotina) but essentially uncharacterized protein. Whether it is a bona fide lipase, another kind of lipid-handling protein, or an EIS1-related protein that only indirectly affects lipids is unresolved, and bears on how many lipases the peroxisomal matrix actually contains.
What would resolve it: In vitro lipase/esterase assays on purified LPX2 against a defined lipid-substrate panel; active-site (GXSXG serine) mutant complementation testing whether catalysis is required to rescue the deletion lipidome phenotype.
Provenance (the field's own admissions):
Gap: LPX2's family placement conflicts with its proposed function: its only recognized sequence family is EIS1/Eisosome1 (a plasma-membrane eisosome protein family), yet it localizes to the peroxisomal matrix and is proposed to act in lipid metabolism. Whether LPX2 retains any EIS1-like (eisosome/membrane-organizing) role, has neofunctionalized after the whole-genome duplication, or does something else entirely is unknown.
OPEN BIOLOGY MF_DARK
What is known: LPX2 is the whole-genome-duplication paralog of EIS1 (SGD), and PANTHER PTHR28298 / Pfam PF12757 place both in the "eisosome protein 1" family. EIS1 is a characterized eisosome component; LPX2 is a peroxisomal-matrix protein with no experimental eisosome role. A GO "eisosome assembly" inference (IBA:GO_Central, present in the UniProt GO cross-references) is propagated from this family and is inconsistent with LPX2's experimental localization.
Significance: Resolving the paralog relationship would clarify whether the eisosome-family assignment (and any downstream IBA "eisosome assembly" annotation) is biologically meaningful for LPX2 or a paralog-driven over-propagation that should be down-weighted.
What would resolve it: Test LPX2 for eisosome localization/assembly phenotypes directly (e.g. Pil1/Lsp1 eisosome imaging in lpx2Ξ and localization of tagged LPX2 relative to eisosomes) and structurally compare the LPX2 and EIS1 domains.
Provenance (the field's own admissions):
Gap: The in-vivo biological role of LPX2 is undefined beyond a lipidomic association. No growth phenotype, defined pathway placement, or contribution to peroxisomal fatty-acid metabolism has been demonstrated specifically for LPX2; the model that peroxisomal lipases release fatty acids for beta-oxidation and maintain peroxisomal membrane morphology is a speculative suggestion proposed for the Lpx1/Lpx2/Fsh3 set, not an LPX2-specific result.
OPEN BIOLOGY BP_DARK
What is known: The one specific phenotype is that lpx2Ξ has the largest glucose-medium lipidome effect (LPG accumulation) in the Yifrach 2022 screen. The functional model that peroxisomal lipases act on the peroxisomal membrane/intraperoxisomal vesicles to release fatty acids for beta-oxidation is stated as a suggestion covering the whole lipase set.
Significance: Without a defined process, LPX2 cannot be placed in a peroxisomal metabolic pathway, and its physiological importance (e.g. under oleate/fatty-acid growth) is unknown.
What would resolve it: Phenotype lpx2Ξ (and lpx1Ξ lpx2Ξ fsh3Ξ combinations) for growth on fatty-acid carbon sources, beta-oxidation flux, and peroxisomal membrane morphology; determine LPX2's peroxisomal import route (it lacks a canonical C-terminal PTS1).
Provenance (the field's own admissions):
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