Human beta two microglobulin: Difference between revisions
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=Structure of human beta two microglobulin= | =Structure of human beta two microglobulin= | ||
==Beta two microglubulin in human class I major histocompatibility complex (MHCb2m)== | ==Beta two microglubulin in human class I major histocompatibility complex (MHCb2m)== | ||
Human β2-Microglobulin is the non-covalently bound light chain of the human class I | Human β2-Microglobulin is the non-covalently bound <scene name='Human_beta_two_microglobulin/Light_chain/2'>light chain</scene> | ||
of the human class I | |||
major histocompatibility complex (MHC-I) | major histocompatibility complex (MHC-I) | ||
<applet load='1duz' size='350' frame='true' align='right' caption='crystal structure of the human class | <applet load='1duz' size='350' frame='true' align='right' caption='crystal structure of the human class | ||
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==Monomeric human b2m (Mhb2m)== | ==Monomeric human b2m (Mhb2m)== | ||
The first crystal structure of Monomeric human b2m (Mhb2m)is solved in 2002. The protein is 99 residue in length and has a | The first crystal structure of Monomeric human b2m (Mhb2m) is solved in 2002 (pdb 1LDS). The protein is 99 residue in length and has a seven-stranded β sandwich fold typical of the Immunoglobulin superfamily. It is stabilized by a single disulfide bond between | ||
seven-stranded β sandwich fold typical of the Immunoglobulin superfamily. It is stabilized by a single disulfide bond between | |||
Cys-25 and Cys-80, which links the two β sheets. | Cys-25 and Cys-80, which links the two β sheets. | ||
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[[Image:Human b2m bound to MHC-1 .jpg.jpg]] [[Image:Momeric human b2m.png]] | [[Image:Human b2m bound to MHC-1 .jpg.jpg]] [[Image:Momeric human b2m.png]] | ||
Fig.1. crystal structures of MHCb2m (left)and Mhb2m (right) | Fig.1. crystal structures of MHCb2m (left) and Mhb2m (right) | ||
Both of the two strucures adopt seven-stranded β sandwich fold with a short C' β strand located in the loop connecting strands C | Both of the two strucures adopt seven-stranded β sandwich fold with a short C' β strand located in the loop connecting strands C | ||
and D. The most significant difference in the ctrystal structures of Mhb2m and MHCb2m involves residues in β strand D and the succeeding loop. When complexed with the MHC heavy chain, residues 50-56 of MHCb2m form two short β strands that separated by a two residue β bulge. These strands (depicted as D1 and D2 in Fig.1) each forms three main-chain-main-chain hydrogen bonds to the adjacent β strand E. The bulge in MHCb2m effectively twists the edge strand, which facilitate its binding to the surface of the heavy chain. However, this β bulge no longer exits in the crytal strucure of Mhb2m. The conformation of D strand in Mhb2m provides an ideal assembly surface, making this edge-strand pair vulnerable to aggregation. The hydrogen-bonding potential of strand D is satisfied by the formation intermolecular interactionswith adjecent molecules, demonstrating the potential for this region to propagate assembly through edge-strand interactions. | and D. The most significant difference in the ctrystal structures of Mhb2m and MHCb2m involves residues in β strand D and the succeeding loop. When complexed with the MHC heavy chain, residues 50-56 of MHCb2m form two short β strands that separated by a two residue β bulge. These strands (depicted as D1 and D2 in Fig.1) each forms three main-chain-main-chain hydrogen bonds to the adjacent β strand E. The bulge in MHCb2m effectively twists the edge strand, which facilitate its binding to the surface of the heavy chain. However, this β bulge no longer exits in the crytal strucure of Mhb2m. The <scene name='Human_beta_two_microglobulin/D_strand/1'>conformation of D strand </scene>in Mhb2m provides an ideal assembly surface, making this edge-strand pair vulnerable to aggregation. The hydrogen-bonding potential of strand D is satisfied by the formation intermolecular interactionswith adjecent molecules, demonstrating the potential for this region to propagate assembly through edge-strand interactions. | ||
In addition, the changes observed in strand D result in differenr orientations of the side chains of residues 50-54. As a result, | In addition, the changes observed in strand D result in differenr orientations of the side chains of residues 50-54. As a result, | ||
His-51 (which points inwards in the structure of MHCb2m) rotates by approximately 180, such that it now points away from the hydrophobic core of the protein. This would remove the second protevtive feature from the edge strand, facilitating further interaction in this region. | His-51 (which points inwards in the structure of MHCb2m) rotates by approximately 180, such that it now points away from the hydrophobic core of the protein. This would remove the second protevtive feature from the edge strand, facilitating further interaction in this region (Fig.2). | ||
[[Image:His51.jpg]] | [[Image:His51.jpg]] | ||
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===A structural trigger=== | ===A structural trigger=== | ||
Alterations of the protein sequence have been used to stimulate the formation of fibrils at neutral pH. Specifically, truncation of six residues from the N-terminal region(DN6), as well as mutation in this region (P5G) or in the B/C or D/E loops ( | Alterations of the protein sequence have been used to stimulate the formation of fibrils at neutral pH. Specifically, truncation of six residues from the N-terminal region(DN6), as well as mutation in this region (P5G) or in the B/C or D/E loops ( | ||
P32A, P32G, D59P) of the protein all enhance its ability to form amyloid in vitro, while substitutions elsewhere in the protein have little effect. These studies have the common feature that they encourage partial unfolding of b2m, allowing the aggregation-prone regions of the polypeptide sequence to be exposed and to participate in intermolecular interactions. | |||
The b2m variants, P32G and P32V, have been used to show that wild-type b2m populates a native-like folding intermediate (called | The b2m variants, P32G and P32V, have been used to show that wild-type b2m populates a native-like folding intermediate (called | ||
IT) en route to the native state that contains a non-native trans Pro32 bond. Increased population of this intermediate in the variant P32G was shown to be concomitant with increased ability of the protein to elongate b2m fibril seeds. Other variants, such as P5G and DN6, also affect isomerisation of the Pro32 peptide bond, promoting population of IT and enabling fibril nucleation at pH 7.0. | IT) en route to the native state that contains a non-native trans Pro32 bond. Increased population of this intermediate in the variant P32G was shown to be concomitant with increased ability of the protein to elongate b2m fibril seeds. Other variants, such as P5G and DN6, also affect isomerisation of the Pro32 peptide bond, promoting population of IT and enabling fibril nucleation at pH 7.0. | ||
