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Possible proteolytic processing of Precerebellin (Cbln 1) by TACE/ADAM-17
This network was generated using Cytoscape V2.2, yFiles/circular layout with a lexically-driven XML plug-in to the Agilent Literature Search, curated and color coded in Adobe Illustrator CS2.
The cerebellum-specific hexadecapeptide cerebellin, originally identified more than 20 years ago, is associated with the synaptosomal fraction and is released upon depolarization in a calcium-dependent manner. It is derived from Cbln1 (cerebellin 1 precursor protein, precerebellin), which has similarity to the globular region of the B chain of human complement component C1q, and is a member of the C1q/tumor necrosis factor (TNF) family of secreted proteins. Interestingly, cerebellin is not liberated from Cbln1 by the classical dibasic amino acid proteolytic-cleavage mechanism seen in many neuropeptide precursors.
A related family member, TNF-alpha, is cleaved (dark blue arrow) from membrane-bound pro-TNF-alpha through the action of TNF-alpha-converting enzyme (TACE, yellow node in the center of the network), a member of a disintegrin and metalloprotease (ADAM) family that is also involved in the proteolysis of the inflammatory cytokine proTGF-alpha and in the regulated ectodomain shedding of angiotensin-converting enzyme 2 (ACE2). It is intriguing that the region preceding the C1q domain of Cbln subfamily proteins (SVRSGS in Cbln1 and Cbln2 and SVRAAN in Cbln4) is similar to the corresponding region of pro-TNF-alpha (AVRSSS), which is recognized by TACE. Since Cbln1-like immunoreactivity is localized in the lysosomal compartment of cerebellar granule cells, proteolysis by TACE-like enzymes (light blue arrow) may represent a mechanism to regulate the amount of Cbln1 secretion in presynaptic neurons. Thus there appear to be parallels between the proteolytic processing of TNF-alpha and Cbln1, including the separation of the globular domain from an N-terminal domain.
Very recently, the complement protein C1q was shown to be expressed transiently by postnatal neurons and to mediate synapse elimination during development. Other C1q family proteins, such as the C1ql subfamily, are also expressed in various regions of the CNS. Furthermore, although adiponectin (AdipoQ, Acrp30), a C1q family protein expressed in mammalian hibernators, is produced in peripheral tissues, it has recently been shown to exert unique functions in specific brain regions.
Understanding of the proteolytic processing and functions of the members of the Cbln subfamily may provide new insights into the roles of C1q family proteins. Cbln1 is a unique synapse organizer regulating and maintaining the pre- and postsynaptic structures at PF(parallel fiber)-Purkinje cell synapses. Cbln2, Cbln3 and Cbln4 are expressed in various regions of the developing and mature brain. Thus, C1q family members may serve as new cytokines that regulate normal and abnormal brain functions. Overall, this information should facilitate the development of novel approaches for the treatment of particular neurological disorders.
A related family member, TNF-alpha, is cleaved (dark blue arrow) from membrane-bound pro-TNF-alpha through the action of TNF-alpha-converting enzyme (TACE, yellow node in the center of the network), a member of a disintegrin and metalloprotease (ADAM) family that is also involved in the proteolysis of the inflammatory cytokine proTGF-alpha and in the regulated ectodomain shedding of angiotensin-converting enzyme 2 (ACE2). It is intriguing that the region preceding the C1q domain of Cbln subfamily proteins (SVRSGS in Cbln1 and Cbln2 and SVRAAN in Cbln4) is similar to the corresponding region of pro-TNF-alpha (AVRSSS), which is recognized by TACE. Since Cbln1-like immunoreactivity is localized in the lysosomal compartment of cerebellar granule cells, proteolysis by TACE-like enzymes (light blue arrow) may represent a mechanism to regulate the amount of Cbln1 secretion in presynaptic neurons. Thus there appear to be parallels between the proteolytic processing of TNF-alpha and Cbln1, including the separation of the globular domain from an N-terminal domain.
Very recently, the complement protein C1q was shown to be expressed transiently by postnatal neurons and to mediate synapse elimination during development. Other C1q family proteins, such as the C1ql subfamily, are also expressed in various regions of the CNS. Furthermore, although adiponectin (AdipoQ, Acrp30), a C1q family protein expressed in mammalian hibernators, is produced in peripheral tissues, it has recently been shown to exert unique functions in specific brain regions.
Understanding of the proteolytic processing and functions of the members of the Cbln subfamily may provide new insights into the roles of C1q family proteins. Cbln1 is a unique synapse organizer regulating and maintaining the pre- and postsynaptic structures at PF(parallel fiber)-Purkinje cell synapses. Cbln2, Cbln3 and Cbln4 are expressed in various regions of the developing and mature brain. Thus, C1q family members may serve as new cytokines that regulate normal and abnormal brain functions. Overall, this information should facilitate the development of novel approaches for the treatment of particular neurological disorders.
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