NEW EMBO MEMBERS' REVIEW: The double life of HMGB1 chromatin protein: architectural factor and extracellular signal

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Abstract
The High Mobility Group Box (HMGB) chromosomal proteins have been known and studied for a long time, but we have only recently started to understand their biological functions. They now have a clear reputation for being important architectural factors: they facilitate the assembly of site‐specific DNA binding proteins to their cognate binding sites within chromatin. Beyond this intranuclear function, they also have an extracellular function, which will be the prime focus of this short review. ### The HMGB family: structure, expression and nuclear function The HMGB family comprises the three proteins HMGB1 (previously HMG1), HMGB2 (previously HMG2) and HMGB3 (previously HMG4 or HMG2b) (Bustin, 2001). The structure of these three proteins is highly conserved (>80% amino acid identity), and their biochemical properties are so far indistinguishable. HMGBs are composed of three different domains. The two homologous DNA binding domains, HMG boxes A and B, are each ∼75 amino acids in length. The C‐terminal domain is highly negatively charged, consisting of a continuous stretch of glutamate or aspartate residues, and is longest in HMGB1 and shortest in HMGB3 (reviewed in Bustin, 1999; Bianchi and Beltrame, 2000). HMGB1 is ubiquitous and only 10 times less abundant than core histones, at ∼106 molecules per typical mammalian cell. Expression of the other two family members is more restricted: HMGB3 is only expressed to a significant amount during embryogenesis (Vaccari et al ., 1998); HMGB2 is widely expressed during embryonic development, but restricted mainly to lymphoid organs and testis in the adult mouse (Ronfani et al ., 2001). The localization of these proteins in most cells is nuclear. In their nuclear identity, HMGB1 and HMGB2 bind to the minor groove of DNA, causing a local distortion of the double helix. They have little or no sequence preference, and they are recruited to the site of action by specific DNA binding proteins. HMGB1 has …