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Here, we present the crystal structure of human HBXIP\u2010C7orf59 dimer (LAMTOR 4\/5) at 2.9\u00a0\u00c5 and identify a phosphorylation site on C7orf59 which modulates its interaction with p18. Additionally, we demonstrate the requirement of HBXIP\u2010C7orf59 to stabilize p18 and allow further binding of MP1\u2010p14. The structure of the dimer revealed an unfolded N terminus in C7orf59 (residues 1\u201315) which was shown to be essential for p18 binding. Full\u2010length p18 does not interact stably with MP1\u2010p14 in the absence of HBXIP\u2010C7orf59, but deletion of p18 residues 108\u2013161 rescues MP1\u2010p14 binding. C7orf59 was phosphorylated by protein kinase A (PKA) <jats:italic>in\u00a0vitro<\/jats:italic> and mutation of the conserved Ser67 residue to aspartate prevented phosphorylation and negatively affected the C7orf59 interaction with p18 both in cell culture and <jats:italic>in\u00a0vitro<\/jats:italic>. C7orf59 Ser67 was phosphorylated in human embryonic kidney 293T cells. PKA activation with forskolin induced dissociation of p18 from C7orf59, which was prevented by the PKA inhibitor H\u201089. Our results highlight the essential role of HBXIP\u2010C7orf59 dimer as a nucleator of pentameric Ragulator and support a sequential model of Ragulator assembly in which HBXIP\u2010C7orf59 binds and stabilizes p18 which allows subsequent binding of MP1\u2010p14.<\/jats:p>","DOI":"10.1002\/2211-5463.12700","type":"journal-article","created":{"date-parts":[[2019,7,17]],"date-time":"2019-07-17T14:28:49Z","timestamp":1563373729000},"page":"1589-1602","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["C7orf59\/LAMTOR4 phosphorylation and structural flexibility modulate Ragulator assembly"],"prefix":"10.1002","volume":"9","author":[{"given":"Nadia","family":"Rasheed","sequence":"first","affiliation":[{"name":"Brazilian Biosciences National Laboratory (LNBio) Brazilian Center for Research in Energy and Materials (CNPEM) Campinas Brazil"},{"name":"Institute of Biology University of Campinas 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