The Drosophila clock protein Timeless is a member of the Arm/HEAT family

In higher eukaryotes, the circadian clock is generated by a system of negative and positive auto-regulatory feedback loops [1]. In Drosophila, the negative limb of this mechanism involves the Timeless (Tim) and Period (Per) proteins, which must physically associate in order to be translocated to the nucleus. Once inside, the Per–Tim heterodimer negatively regulates the expression of the per and tim genes. Per is a founder member of the PAS (Per-Arnt-Sim) protein family [2] and contains two PAS domains that are involved in protein dimerization. The Drosophila genome encodes two different tim genes, the clock relevant dtim, and a second, ancestral gene, dtim2 or timeout, which is the true orthologue of mammalian Tim [3.] and [4.]. mTim does not appear to play a significant role in the murine clock [5]. No protein domains have yet been identified in Tim or Tim2, so in order to gain some insight into the possible biochemical and conformational nature of Tim proteins, we have applied structural predictions that suggest them to be members of the Arm/HEAT family.