Working model. (A) Long-range tethering is mediated by coiled-coil Golgin family tethers and multisubunit tethering complexes (MTC’s). Flexibility or buckling of long-range tethers allows the vesicle to dwell in the region near Sly1 so that handoff can occur. (B) Mechanism of close-range tethering. Sly1 is anchored to the N-terminal domain of the Qa-SNARE on the target membrane. Note that in the closed ground state, the loop and helix α21 (magenta) occlude the sec22 binding site on the Sly1 SNARE templating domain (yellow). Binding of α21 to an incoming vesicle’s membrane pulls open the autoinhibitory loop and tethers the vesicle to Sly1, likely in a spatial orientation optimal for Sec22 binding to Sly1’s SNARE templating domain (yellow). In panels ii and iii, helix α21 is shown but the unstructured portion of the loop is omitted for clarity. (C) The Sly1 loop is conformationally heterogeneous in the crystal structure (PDB ID 1MQS). Temperature (B) factors in the Sly1 crystal are shown by color and backbone trace thickness. The highest disorder is in α20–α21, the thick red peptide segment.