Comparative binding of biotinylated neurotrophins to ?2-macroglobulin family of proteins: Relationship between cytokine-binding and neuro-modulatory activities of the macroglobulins

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Abstract
Human α2‐macroglobulin (α2M), pregnancy zone protein (PZP), rat α1M and acute‐phase rat α2M belong to the α2M gene family of proteins, which can react covalently with nucleophilic monoamines to yield monoamine‐activated (MA) macroglobulins. The MA forms of human α2M, PZP and rat α2M have been demonstrated previously to inhibit various neurotrophin‐promoted neuronal activities, whereas MA‐α1M is neurostimulatory and all native macroglobulins are generally inactive. The mechanism of neuromodulation is unknown, but it has been postulated that MA macroglobulins might inhibit neurons via their binding and sequestration of neurotrophins. This study employed a novel biotinylation‐Western blot technique to compare the neurotrophin‐binding properties of the four macroglobulins, and to correlate their binding activities with their known neuro‐modulatory activities. In comparison with their respective native counterparts, human and rat MA‐α2M bound slightly more NGF, but significantly less BDNF or NT‐3. Native human α2M and PZP in general have no neuro‐modulatory activity, but native PZP bound significantly more NGF, BDNF or NT‐3 than either native α2M or MA‐α2M, which is neuro‐inhibitory. It is known that MA‐PZP is neuro‐inhibitory, but it fails to bind more NGF, BDNF, or NT‐3 than native PZP. MA‐α1M is the only macroglobulin known to stimulate NGF‐promoted neurite outgrowth, but it bound NGF with similar affinities as native α1M and rat α2M; in addition, it bound significantly less BDNF or NT‐3 than native α1M. All the bindings were non‐covalent and appeared specific. In conclusion, PZP and rat macroglobulins are versatile carriers of neurotrophins with diverse binding capacities, and the neurotrophin‐binding property does not appear to mediate the neuro‐modulatory activity of these human and rat macroglobulins.

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