title: Macromolecular crowding induces holo α-lactalbumin aggregation by converting to its apo form.
abstract: Macromolecular crowding has been shown to have an exacerbating effect on the aggregation propensity of amyloidogenic proteins; while having an inhibitory effect on the non-amyloidogenic proteins. However, the results concerning aggregation propensity of non-amyloidogenic proteins have not been convincing due to the contrasting effect on holo-LA, which despite being a non-amyloidogenic protein was observed to aggregate under crowded conditions. In the present study, we have extensively characterized the crowding-induced holo-LA aggregates and investigated the possible mechanism responsible for the aggregation process. We discovered that macromolecular crowding reduces the calcium binding affinity of holo-LA resulting in the formation of apo-LA (the calcium-depleted form of holo-LA) leading to aggregate formation. Another finding is that calcium acts as a chaperone capable of inhibiting and dissociating crowding-induced holo-LA aggregates. The study has a direct implication to Alzheimer Disease as the results invoke a new mechanism to prevent Aβ fibrillation.
authors.affiliation: Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India.
authors.forename: Shruti
authors.initials: S
authors.lastname: Mittal
authors.affiliation: Dr. B. R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, India.
authors.forename: Laishram Rajendrakumar
authors.initials: LR
authors.lastname: Singh
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002417:Cattle; D007768:Lactalbumin / Q000737:chemistry / Q000378:metabolism*; D066329:Protein Aggregates; D011485:Protein Binding; D011489:Protein Denaturation; D017433:Protein Structure, Secondary
chemical_list: D066329:Protein Aggregates; D007768:Lactalbumin; D002118:Calcium