The discovery of the Nogo-B specific receptor NgBR significantly advanced our understanding of the molecular mechanism underlying the diverse functions of Nogo proteins. In particular, the key role of the AmNogoB-NgBR interaction in mediating chemotaxis and 3D tube formation ranks NgBR as an extremely promising target for design of agonists or antagonists of this pathway to modulate vascular remodeling and angiogenesis [7]. Previously we have conducted a systematical characterization of the structural and binding properties of Nogo proteins [6], [14], [15], [16] and [24]. In the present study, we initially attempted to determine the structure of NgBR. To our big surprise, the bioinformatics, CD and NMR characterization reveals that the NgBR ectodomain is a member of the intrinsically unstructured protein (IUP) family. Previously, the very unusual properties of the intrinsically unstructured family of proteins have been proposed to be advantageous for special categories of biological functions including signal transduction, regulation, cytoskeletonal organization, protein–DNA recognition, human cancer, P505-15 as well as generating/maintaining membrane structure [10], [11], [12], [13], [14], [19], [20], [25], [26], [27] and [28]. However, the commitment of an intrinsically unstructured protein as the ectodomain of a transmembrane receptor was rarely reported. The ectodomain of the transmembrane β-dystroglycan was characterized to be an intrinsically unstructured protein [29]. However, the known function of the β-dystroglycan ectodomain is to constitute a dystroglycan complex by binding α-dystroglycan which is separated from β-dystroglycan by a posttranslational cleavage of a single proprotein at Ser654. To this end, β-dystroglycan is usually not considered to be a transmembrane receptor [30]. Our current finding raises an intriguing question as how the intrinsically unstructured NgBR ectodomain functions. It appears that there may be three possible mechanisms. The first one is that the NgBR ectodomain becomes well-structured upon binding to Nogo-B or other partners. Alternatively it is also possible that unlike the classic receptor ectodomains, the NgBR ectodomain may function more like a scaffold to utilize short motifs to assemble a variety of binding partners over the cell surface. The third one is that similar to β-dystroglycan, the NgBR ectodomain is a component of a multi-component receptor complex [7]. However, if only considering its interaction with Nogo-B, it is very unlikely that upon binding they will form a well-structured complex as both NgBR ectodomain and Nogo-B N-terminus are highly unstructured as well as proline-rich [14]. Certainly, intense studies are demanded to address the implications of this unusual property of NgBR in the future.