{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T18:15:43Z","timestamp":1788372943240,"version":"build-2803163510"},"reference-count":83,"publisher":"National Academy of Sciences","issue":"36","license":[{"start":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:00:00Z","timestamp":1788307200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,9,8]]},"abstract":"<jats:p>\n                    Many insects manipulate plants by injecting effector proteins. In one extreme example of this molecular \u201chijacking,\u201d\n                    <jats:italic toggle=\"yes\">Hormaphis cornu<\/jats:italic>\n                    aphids inject bicycle proteins into\n                    <jats:italic toggle=\"yes\">Hamamelis virginiana<\/jats:italic>\n                    , contributing to the development of novel organs called galls. Bicycle proteins share no amino acid sequence similarity with proteins of known function. Here, we report the crystal structures of two divergent bicycle proteins. Both proteins contain saposin-like folds: one with multiple disulfide bonds exhibits a swapped domain topology; the other has no disulfide bonds and possesses two distinct, tandem domains. To explore the structural evolution of bicycle proteins, we attempted to predict bicycle protein structures with Alphafold2 (AF2) and other deep learning programs. While AF2 did not recover the two experimental structures using existing databases, it succeeded when provided with multiple sequence alignments (MSAs) of protein sequences from newly sequenced closely related species. Using this approach, we generated 2,400 high-confidence bicycle protein predictions from seven aphid species. While all aphid bicycle proteins contain predicted saposin-like folds, they display a vast diversity of structural and physicochemical properties. While this diversity thwarts prediction of conserved functions encoded in structure, it suggests that bicycle proteins have evolved to target diverse plant processes and\/or to evade plant immune surveillance. Our extension of AF2 with custom MSAs of proteins from closely related species provides a generalizable, powerful approach for predicting structures of rapidly evolving protein families.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2609639123","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T17:36:43Z","timestamp":1788370603000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Rapidly evolving aphid gall effector proteins exhibit saposin-like folds"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3033-8438","authenticated-orcid":false,"given":"Fatema","family":"Bhinderwala","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01an3r305","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Structural Biology, University of Pittsburgh School of Medicine","place":["Pittsburgh"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4244-0140","authenticated-orcid":false,"given":"Aishwarya","family":"Korgaonkar","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013sk6x84","id-type":"ROR","asserted-by":"publisher"}],"name":"Janelia Research Campus, Janelia Research Campus, HHMI","place":["Ashburn"]},{"name":"HHMI","place":["Kansas City"]},{"id":[{"id":"https:\/\/ror.org\/04bgfm609","id-type":"ROR","asserted-by":"publisher"}],"name":"Stowers Institute for Medical Research","place":["Kansas City"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kota","family":"Gopalakrishna","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013sk6x84","id-type":"ROR","asserted-by":"publisher"}],"name":"Janelia Research Campus, Janelia Research Campus, HHMI","place":["Ashburn"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8637-3515","authenticated-orcid":false,"given":"Thomas C.","family":"Mathers","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/055zmrh94","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Crop Genetics, John Innes Centre","place":["Norwich, United Kingdom"]},{"id":[{"id":"https:\/\/ror.org\/05cy4wa09","id-type":"ROR","asserted-by":"publisher"}],"name":"Tree of Life, Wellcome Sanger Institute","place":["Hinxton, Cambridge, United Kingdom"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4640-2323","authenticated-orcid":false,"given":"Shuji","family":"Shigenobu","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05q8wtt20","id-type":"ROR","asserted-by":"publisher"}],"name":"Laboratory of Evolutionary Genomics, Trans-Scale Biology Center, National Institute for Basic Biology","place":["Myodaiji, Okazaki, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3645-9935","authenticated-orcid":false,"given":"J. 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Bhinderwala Hamamelistes spinosus Genome sequencing and assembly. NCBI BioProject. https:\/\/www.ncbi.nlm.nih.gov\/bioproject\/?term=PRJNA1492693. Deposited 9 July 2026."},{"key":"e_1_3_4_81_2","unstructured":"F. Bhinderwala Hormaphis betulae Genome sequencing and assembly. NCBI BioProject. https:\/\/www.ncbi.nlm.nih.gov\/bioproject\/?term=PRJNA1492206. Deposited 8 July 2026."},{"key":"e_1_3_4_82_2","unstructured":"F. Bhinderwala Hormaphis hamamelidis. NCBI BioProject. https:\/\/www.ncbi.nlm.nih.gov\/bioproject\/PRJNA1491490\/. Deposited 7 July 2026."},{"key":"e_1_3_4_83_2","unstructured":"D. Stern Genome annotations for studies of bicycle protein evolution. Figshare. https:\/\/doi.org\/10.6084\/m9.figshare.33000401. 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