biostudies-literatureLin HLFritz B. Burns FoundationNIA NIH HHSBrigham Young UniversityNational Institute on Aging2920-2935https://www.ebi.ac.uk/biostudies/studies/S-EPMC9724711biostudies-literatureUnknown21(12)Many of the diseases that plague society today are driven by a loss of protein quality. One method to quantify protein quality is to measure the protein folding stability (PFS). Here, we present a novel mass spectrometry (MS)-based approach for PFS measurement, iodination protein stability assay (IPSA). IPSA quantifies the PFS by tracking the surface-accessibility differences of tyrosine, histidine, methionine, and cysteine under denaturing conditions. Relative to current methods, IPSA increases protein coverage and granularity to track the PFS changes of a protein along its sequence. To our knowledge, this study is the first time the PFS of human serum proteins has been measured in the context of the blood serum (in situ). We show that IPSA can quantify the PFS differences between differeJournal of proteome researchQuantifying In Situ Structural Stabilities of Human Blood Plasma Proteins Using a Novel Iodination Protein Stability Assay.PMC9724711R01 AG066874R01AG066874Haderlie CTBerg MPrice JCMoody JDBateman TMZackrison MJJames IPark JSTseng YJDaley SALin HLHyer CDZuniga Pina NRfalseQuantifying In Situ Structural Stabilities of Human Blood Plasma Proteins Using a Novel Iodination Protein Stability Assay.Many of the diseases that plague society today are driven by a loss of protein quality. One method to quantify protein quality is to measure the protein folding stability (PFS). Here, we present a novel mass spectrometry (MS)-based approach for PFS measurement, iodination protein stability assay (IPSA). IPSA quantifies the PFS by tracking the surface-accessibility differences of tyrosine, histidine, methionine, and cysteine under denaturing conditions. Relative to current methods, IPSA increases protein coverage and granularity to track the PFS changes of a protein along its sequence. To our knowledge, this study is the first time the PFS of human serum proteins has been measured in the context of the blood serum (in situ). We show that IPSA can quantify the PFS differences between differe2022-01-01T00:00:00Z2022 Dec2026-05-28T02:06:35.122Z2025-04-06T08:03:36.418ZS-EPMC97247113635621510.1021/acs.jproteome.2c00323