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Despite extensive research to understand the factors contributing to amyloidogenesis, accurately predicting whether a given protein will form amyloids under specific conditions remains a formidable challenge. In this study, we have conducted a comprehensive analysis to understand the amyloidogenic tendencies within a dataset containing 1828 (348 amyloidogenic and 1480 non\u2010amyloidogenic) antibody light chain variable region (<jats:italic>V<\/jats:italic><jats:sub>L<\/jats:sub>) sequences obtained from the AL\u2010Base database. Physicochemical and structural features often associated with protein aggregation, such as net charge, isoelectric point (pI), and solvent\u2010exposed hydrophobic regions did not reveal a consistent association with the aggregation capability of the antibody light chains. However, the solvent\u2010exposed aggregation\u2010prone regions (APRs) occur with higher frequencies among the amyloidogenic light chains when compared with the non\u2010amyloidogenic ones, with the difference ranging from 2% to 15% at various relative solvent\u2010accessible surface area (rASA) cutoffs. We have, for the first time, identified structural gatekeeping residues around the APRs and assessed their impact on the amyloidogenicity of the antibody light chains. The non\u2010amyloidogenic light chains contain these structural gatekeeper residues vicinal to their APRs more often than the amyloidogenic ones. We observed that the rASA cutoff of 35% is optimal for identifying the surface\u2010exposed APRs, and a 4\u2009\u00c5 distance cutoff from the APR motif(s) is optimal for identifying the structural gatekeeper residues. Moreover, lambda light chains were found to contain solvent\u2010exposed APRs more often and surrounded by fewer gatekeepers, rendering them more susceptible to aggregation. The insights gained from this report have significant implications for understanding the molecular origins of light\u2010chain amyloidosis in humans and the design of aggregation\u2010resistant therapeutic antibodies.<\/jats:p>","DOI":"10.1002\/prot.26815","type":"journal-article","created":{"date-parts":[[2025,3,11]],"date-time":"2025-03-11T23:39:47Z","timestamp":1741736387000},"page":"1451-1464","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Investigating Local Sequence\u2010Structural Attributes of Amyloidogenic Light Chain Variable Domains"],"prefix":"10.1002","volume":"93","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3822-8081","authenticated-orcid":false,"given":"Puneet","family":"Rawat","sequence":"first","affiliation":[{"name":"University of Oslo and Oslo University Hospital  Oslo Norway"},{"name":"Protein Bioinformatics Lab, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences Indian Institute of Technology Madras  Chennai India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0172-3716","authenticated-orcid":false,"given":"R.","family":"Prabakaran","sequence":"additional","affiliation":[{"name":"Protein Bioinformatics Lab, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences Indian Institute of Technology Madras  Chennai India"},{"name":"Department of Biology Emory University  Atlanta Georgia USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divya","family":"Sharma","sequence":"additional","affiliation":[{"name":"Protein Bioinformatics Lab, Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences Indian Institute of Technology Madras  Chennai India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasanth","family":"Mandala","sequence":"additional","affiliation":[{"name":"Biotherapeutics Discovery Boehringer\u2010Ingelheim Inc  Ridgefield Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Greiff","sequence":"additional","affiliation":[{"name":"University of Oslo and Oslo University Hospital  Oslo Norway"},{"name":"Imprint Labs, LLC  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2840-6398","authenticated-orcid":false,"given":"Sandeep","family":"Kumar","sequence":"additional","affiliation":[{"name":"Biotherapeutics Discovery Boehringer\u2010Ingelheim Inc  Ridgefield Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1776-4096","authenticated-orcid":false,"given":"M. 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