Myelin Basic Protein, A Saucy Molecule With High Responsiveness to the Environment or Just an Unusual Membrane Protein? - Molecules: Nucleation, Aggregation and Crystallization - page 177

Post-Translational Modifications of MBP

Up to the present time, very little is known about the native three-dimensional
MBP conformation. This can be ascribed also to the difficulty to crystallize
MBP, even after an exhaustive number of experiments [(Sedzik, Kirschner,
1992); BIOMED-2 (1996-1999)]. As we will discuss later, this is certainly
due to the high heterogeneity of MBP isoforms as many charge and mass iso-
mers derive from numerous post-translational modifications [N-terminal acy-
lation (Ala 1), phosphorylation (Ser 7, 12, 19, 56, 71, 102, 115, 136, 151, 161,
163, 165; Thr 17, 20, 95, 98, 149), deimination (Arg 5, 9, 25, 31, 33, 43, 49,
54, 65, 79, 97, 113, 122, 130, 159, 162, 169, 170), deamidation (Gln 8, 81,
103, 121, 147), methylation (Arg 107, 159) oxidation (Met 21), insertion of
GalNac (Thr 95, 98) and ADP ribosylation (Arg 9, 54)] with reference to the
human MBP sequence (Harauz et al ., 2004; DeBruin, Harauz, 2007).
The main result of post-translational modifications of the 18.5 kDa MBP

(pI 10.6) is the occurrence of charge isomers termed C1-C2-C3-C4-C5-C6-

C8 and the consequent reduction of net positive charge from

=

13 from
C1 to C8. C1 and C2 are the least modified and most positively charged iso-
mers. The deiminated (citrullinated) component C8 occurs in greater amounts
in patients with MS (Moscarello et al ., 1994). Besides post-translational mod-
ifications, association with different types of ligands (including lipids) and
type of location are a further cause of great diversification of MBP.
Post-translational modifications may serve to direct MBP to different
environments: for example, the 20.2 and 21.5 kDa isoforms of MBP move
to the nucleus if they become phosphorylated (Pedraza et al ., 1997),
whereas the distribution of the 18.5 kDa MBP in the membrane is depend-
ent on the type of modification (phosphorylation, methylation or deimina-
tion) (DeBruin et al ., 2005; Carlone et al ., 2005; DeBruin, Harauz, 2007).

+ 19 to +

Is MBP a Natively Unfolded Protein?

The absence of structure in the acid-extracted molecule

To decide whether MBP is a natively unfolded protein, it is necessary to
establish what its native environment is. MBP was purified for the first