Fig 1: Domain organization of ESCRT-III and MIT domain-containing proteins.(A) Generalized ESCRT-III schematic, depicting the conserved helical core domain and the variable C-terminal tail that contains MIT-interacting Motif (MIM) elements. (B) Human proteins with MIT domains, grouped by enzymatic categories. Three dimensional structures (PDB IDs in parenthesis) are available for the MIT domains from human VPS4A (1YXR, 2JQ9, 2K3W), VPS4B (2JQH, 2JQK, 4U7Y, 1WRO, 2CPT), SPASTIN (3EAB), USP8 (2A9U), AMSH (2XZE), NRBF2 (4ZEY), LIP5 (2LXL, 2LXM, 4TXP, 4TXQ, 4TXR, 4U7E), SPARTIN (4U7I), MITD1 (4A5X), and ULK3 MIT2 (4WZX). Abbreviations: MIT, Microtubule Interacting and Trafficking; MTB, Microtubule Binding Domain; S/T Kinase, Serine/Threonine Kinase domain; PSK, Pseudokinase domain; PX, Phosphoinositide binding domain; CysPc, Calpain protease domain; USP, Ubiquitin Specific Protease Domain; PLD, Phospholipase D-like domain; VSL, Vta1-SBP1-LIP5 domain; JAMM, JAB1/MPN/Mov34 metalloenzyme domain; CBSW, calpain-type beta-sandwich domain. (C) Gallery showing the different types of binding interactions formed between MIT domains (blue) and MIM elements (green). For clarity, the three helix bundles of the different MIT domains are shown in approximately equivalent orientations. Type 1 interaction: a helical MIM binds in the groove between MIT helices 2 and 3 (H2/H3 groove), and is oriented parallel to MIT helix 3. Type 2 interaction: the MIM forms an extended strand that binds in the MIT H1/H3 groove, parallel to MIT helix 3. Type 3 interaction: a helical MIM binds in the MIT H1/3 groove, parallel to MIT helix 3. Type 4 interaction: Similar to Type 1, except that the longer MIM helix binds lower in the H2/H3 groove and interacts with the H2/H3 loop. Type 5 interaction: Two MIM helices and adjacent linkers wrap nearly completely around the MIT domain. Type 6 interaction: a mixed helix/strand MIM element binds in the MIT H1/3 groove, antiparallel to MIT helix 3. Type 7 interaction: a helical MIM element binds in the MIT 2/3 groove, antiparallel to helix 3. The specific complexes shown in the figure are labeled below, together with their PDB accession codes.