Serum Albumin Domain Structures in Human Blood Serum by Mass Spectrometry and Computational Biology.

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Cross-linking density has been typically limited by the chemical selectivity of the standard cross-linking reagents that are commonly used for protein cross-linking. We have implemented the use of a heterobifunctional cross-linking reagent, sulfosuccinimidyl 4,4'-azipentanoate (sulfo-SDA), combining a traditional sulfo-N-hydroxysuccinimide (sulfo-NHS) ester and a UV photoactivatable diazirine group. This diazirine yields a highly reactive and promiscuous carbene species, the net result being a greatly increased number of cross-links compared with homobifunctional, NHS-based cross-linkers. We present a novel methodology that combines the use of this high density photo-cross-linking data with conformational space search to investigate the structure of human serum albumin domains, from purified samples, and in its native environment, human blood serum. Our approach is able to determine human serum albumin domain structures with good accuracy: root-mean-square deviation to crystal structure are 2.8/5.6/2.9 Å (purified samples) and 4.5/5.9/4.8Å (serum samples) for domains A/B/C for the first selected structure; 2.5/4.9/2.9 Å (purified samples) and 3.5/5.2/3.8 Å (serum samples) for the best out of top five selected structures. Our proof-of-concept study on human serum albumin demonstrates initial potential of our approach for determining the structures of more proteins in the complex biological contexts in which they function and which they may require for correct folding. Data are available via ProteomeXchange with identifier PXD001692.", "claims": [{"id": "claim-method", "statement": "False discovery rates (FDR) were estimated following a modified target-decoy search strategy (22, 26).", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:26385339", "locator": "sections[12] \"Mass Spectrometry and Data Analysis\" paragraph 4", "quote": "False discovery rates (FDR) were estimated following a modified target-decoy search strategy (22, 26)."}], "state": "complete"}, {"id": "claim-data-access", "statement": "Data are available via ProteomeXchange with identifier PXD001692.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:26385339", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "Data are available via ProteomeXchange with identifier PXD001692."}], "state": "complete"}, {"id": "claim-target-result", "statement": "The study’s headline result was that photo-cross-linking/mass spectrometry combined with conformational space search determined HSA domain structures with first-selected RMSDs of 2.8/5.6/2.9 Å for purified samples and 4.5/5.9/4.8 Å for serum samples; false discovery rates were estimated using a modified target-decoy search strategy, and the source data are deposited in ProteomeXchange through PRIDE under identifier PXD001692.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:26385339", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "Our approach is able to determine human serum albumin domain structures with good accuracy: root-mean-square deviation to crystal structure are 2.8/5.6/2.9 Å (purified samples) and 4.5/5.9/4.8Å (serum samples) for domains A/B/C for the first selected structure; 2.5/4.9/2.9 Å (purified samples) and 3.5/5.2/3.8 Å (serum samples) for the best out of top five selected structures."}, {"asset": "source:pmid:26385339", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "Data are available via ProteomeXchange with identifier PXD001692."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "The study’s headline result was that photo-cross-linking/mass spectrometry combined with conformational space search determined HSA domain structures with first-selected RMSDs of 2.8/5.6/2.9 Å for purified samples and 4.5/5.9/4.8 Å for serum samples; false discovery rates were estimated using a modified target-decoy search strategy, and the source data are deposited in ProteomeXchange through PRIDE under identifier PXD001692.", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:26385339"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. 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