During the development of brain in mammals, neurons are required to migrate from their origin to their final position and form a highly ordered layer structure. Reelin protein is a key molecule that regulates neuronal migration and brain development. The mice lacking reelin protein, called "reeler mouse" exhibit ataxia, tremors, imbalance, and a typical reeling gait and their brain structure are abnormal. The significant role of reelin in brain development in human as well as in mouse has been reported. Disruption of the reelin gene in human results in abnormal development of brain. Reelin protein is secreted from several populations of neurons, and acts on target neurons through its receptors on cell surface. The members of low density lipoprotein receptor gene family, apolipoprotein E receptor 2 and have been identified as reelin receptors.
Reelin is a large secreted glycoprotein composed of 3461 amino acids in mouse and has eight tandem repeats, named "reelin repeat" of 350-390 amino acid residues. Each reelin repeat has an epidermal growth factor (EGF) module at its center, flanked by two subrepeats A and B (Figure 1).
Subrepeats A and B have weak similarity in the amino acid sequence to each other. Shown in Figure 2 is the overall structure of the third reelin repeat (R3).
The most striking feature of the reelin repeat structure is the "horse-shoe" like subdomain arrangement where subrepeats A and B directly contact despite the EGF module disruption. N terminus of the reelin repeat is located at the opposed side of C terminus, which allows reelin repeats to be tandemly connected. As suggested by the similarity in the amino acid sequence, subrepeats A and B are structurally very similar. Each subrepeat is composed of eleven β-strands forming anti-parallel β-sheets in a jellyroll fold that is similar to that of carbohydrate binding domain (CBD) found in many other proteins such as lectins and enzymes. Subrepeats of reelin have one calcium ion-binding site that is also commonly found in other CBDs.
It has been reported that the fragment composed of the fifth and the sixth reelin repeats (R5-R6) is capable of binding to receptor. Shown here in Figure 3 is the overall structure of the R5-R6 fragment.
The most striking feature of the R5-R6 structure is the arrangement of two reelin repeats, where R5 and R6 are arranged side by side, connected by a short linker segment (eight residues), with no space between them. Another feature of the R5-6 structure is the presence of bound two zinc ions. However, it is unclear whether these bound zinc ions have any role in reelin-mediated signaling.
Protein Data Bank (PDB)
Nogi, T. Yasui, N. Hattori, M. Iwasaki, K. Takagi, J.; "Structure of a signaling-competent reelin fragment revealed by X-ray crystallography and electron tomography"; Embo J.; (2006) 25:3675-3683 PubMed:16858396.
author: Norihisa Yasui