(A) Domain schematics of SNX1 and SNX27 showing the newly identified interaction. (B) Model of full-length SNX1 generated using AlphaFold2; the two acidic motifs (DIF and DLF) found in the flexible N-terminus are highlighted as sticks. (C, D) Two different views of the SNX27 FERM domain (PDB: 7CT1) modeled with SNX1 acidic motifs. The left-land view (C) shows SNX1 in the same orientation as panel (B). The right-hand (D) view shows SNX1 rotated by 180 degrees. An X-ray crystal structure using a fusion construct revealed a DLF motif binds the SNX27 FERM pocket composed of a hydrophobic groove with surrounding basic (R492, K496, R498) residues; this is similar to the view shown in (D). There is a second location on SNX27 FERM that contains a hydrophobic groove with flanking basic residues (R290, K292, K293). Both pockets are shown in dashed circles. The second proposed pocket should be tested to determine whether it could allow both motifs to bind simultaneously (discussed further in text).