{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T02:15:06Z","timestamp":1789697706843,"version":"4.0.1"},"reference-count":33,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,16]],"date-time":"2025-09-16T00:00:00Z","timestamp":1757980800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, ROC","doi-asserted-by":"publisher","award":["MOST 111-2113-M-715-001"],"award-info":[{"award-number":["MOST 111-2113-M-715-001"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, ROC","doi-asserted-by":"publisher","award":["MMC-RD-110-1B-P015"],"award-info":[{"award-number":["MMC-RD-110-1B-P015"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, ROC","doi-asserted-by":"publisher","award":["MMC-RD-111-2B-P004"],"award-info":[{"award-number":["MMC-RD-111-2B-P004"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, ROC","doi-asserted-by":"publisher","award":["MMC-RD-111-2B-P005"],"award-info":[{"award-number":["MMC-RD-111-2B-P005"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014804","name":"Mackay Medical College","doi-asserted-by":"publisher","award":["MOST 111-2113-M-715-001"],"award-info":[{"award-number":["MOST 111-2113-M-715-001"]}],"id":[{"id":"10.13039\/501100014804","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014804","name":"Mackay Medical College","doi-asserted-by":"publisher","award":["MMC-RD-110-1B-P015"],"award-info":[{"award-number":["MMC-RD-110-1B-P015"]}],"id":[{"id":"10.13039\/501100014804","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014804","name":"Mackay Medical College","doi-asserted-by":"publisher","award":["MMC-RD-111-2B-P004"],"award-info":[{"award-number":["MMC-RD-111-2B-P004"]}],"id":[{"id":"10.13039\/501100014804","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100014804","name":"Mackay Medical College","doi-asserted-by":"publisher","award":["MMC-RD-111-2B-P005"],"award-info":[{"award-number":["MMC-RD-111-2B-P005"]}],"id":[{"id":"10.13039\/501100014804","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The GXXXG motif, also called the glycine zipper, is a common sequence pattern that facilitates tight packing of secondary structures, especially through helix\u2013helix interactions in both membrane and soluble proteins. However, its overall distribution, sequence variation, and structural preferences depending on context are not fully understood. Here, we offer a detailed, large-scale analysis of GXXXG motifs, examining over 25,000 unique UniProt sequences with structural data. We classified the motifs as transmembrane (TM), non-transmembrane (non-TM), or shared, based on their TM coverage, and analyzed them via statistical models, diversity measures, and compositional profiling. Our findings show that \u226560% TM coverage is a reliable cutoff to distinguish TM-specific motifs, which tend to have less sequence diversity, lower entropy, more hydrophobic residues (notably leucine, isoleucine, and valine), and rank\u2013frequency distributions that follow a heavy-tailed pattern, indicating strong selective pressure. Conversely, non-TM motifs are more varied, with higher entropy and a preference for polar or flexible residues. Shared motifs have intermediate features, reflecting their functional versatility. Power-law and Zipfian analyses support the distinct statistical signatures of TM and non-TM motifs at the 60% coverage threshold. These results enhance our understanding of the structural and evolutionary roles of the GXXXG motif, setting clear standards for identifying TM-specific motifs and offering insights into membrane protein biology, synthetic design, and functional annotation.<\/jats:p>","DOI":"10.3390\/ijms26189014","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T05:59:51Z","timestamp":1758088791000},"page":"9014","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Comprehensive Analysis of the GXXXG Motif Reveals Structural Context-Dependent Diversity and Composition Across Proteins"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4439-8033","authenticated-orcid":false,"given":"Chi-Jen","family":"Lo","sequence":"first","affiliation":[{"name":"Metabolomics Core Laboratory, Heathy Aging Research Center, Chang Chung University, Taoyuan 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting-Fong","family":"Lin","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, MacKay Medical University, New Taipei City 250, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue-Li","family":"Juang","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, MacKay Medical University, New Taipei City 250, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2443-7365","authenticated-orcid":false,"given":"Yi-Cheng","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Medicine, College of Medicine, MacKay Medical University, New Taipei City 250, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1006\/jmbi.1999.3489","article-title":"The GxxxG motif: A framework for transmembrane helix-helix association","volume":"296","author":"Russ","year":"2000","journal-title":"J. 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