We are analyzing features of the K+ channel subunit proteins that are critical for function and regulation of these proteins. Our studies show biochemically that subunit proteins from the Shaker and Shaw subfamilies fail to assemble into a heteromultimer. The basis for this incompatibility is the sequences contained within the T1 assembly domain. For a subunit protein to heteromultimerize with a Shaker subunit protein, two regions within the T1 domain, A and B, must be of the Shaker subtype. Finally, we show that the incompatibility of a Shaw A region for assembly with a Shaker protein depends upon the composition of a 30 amino acid conserved sequence in the A region.