Limits...
Structural basis for the recognition and cleavage of histone H3 by cathepsin L.

Adams-Cioaba MA, Krupa JC, Xu C, Mort JS, Min J - Nat Commun (2011)

Bottom Line: Canonical substrate-cathepsin L interactions are observed in the complex between the protease and the histone H3 peptide.Systematic analysis of the impact of posttranslational modifications at histone H3 on substrate selectivity suggests cathepsin L to be highly accommodating of all modified peptides.This is the first report of cathepsin L-histone H3 interaction and the first structural description of cathepsin L in complex with a substrate.

View Article: PubMed Central - PubMed

Affiliation: Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada.

ABSTRACT
Proteolysis of eukaryotic histone tails has emerged as an important factor in the modulation of cell-cycle progression and cellular differentiation. The recruitment of lysosomal cathepsin L to the nucleus where it mediates proteolysis of the mouse histone H3 tail has been described recently. Here, we report the three-dimensional crystal structures of a mature, inactive mutant of human cathepsin L alone and in complex with a peptide derived from histone H3. Canonical substrate-cathepsin L interactions are observed in the complex between the protease and the histone H3 peptide. Systematic analysis of the impact of posttranslational modifications at histone H3 on substrate selectivity suggests cathepsin L to be highly accommodating of all modified peptides. This is the first report of cathepsin L-histone H3 interaction and the first structural description of cathepsin L in complex with a substrate.

Show MeSH

Related in: MedlinePlus

Sequence and structural conservation among human cathepsins L and V and murine cathepsin L.(a) Structure-based sequence alignment of cathepsins L and V. White residues on red background indicate identical residues, red residues on white represent similar residues and the other residues are coloured in black. (b) Surface representation of human cathepsins L, V and murine cathepsin L. The structure of murine cathepsin L is modelled based on human cathepsin L. The histone H3 peptide in human cathepsin L complex structure is superimposed to human cathepsin V and murine cathepsin L structures for comparison.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3105313&req=5

f3: Sequence and structural conservation among human cathepsins L and V and murine cathepsin L.(a) Structure-based sequence alignment of cathepsins L and V. White residues on red background indicate identical residues, red residues on white represent similar residues and the other residues are coloured in black. (b) Surface representation of human cathepsins L, V and murine cathepsin L. The structure of murine cathepsin L is modelled based on human cathepsin L. The histone H3 peptide in human cathepsin L complex structure is superimposed to human cathepsin V and murine cathepsin L structures for comparison.

Mentions: In the human genome, there are two similar proteases that had been called cathepsin L. The original cathepsin L was first isolated in the late 1970s28. In 1998, a second human protease was cloned29, which was first named as cathepsin L2 but is now referred to as cathepsin V. Human cathepsin V is very similar to cathepsin L in sequence (Fig. 3). The genes for human cathepsin V and cathepsin L are in close proximity on chromosome 9, hinting that they might come from recent gene duplication. In the case of the mouse, it seems that only one cathepsin L form exists, and it is intermediate between human cathepsin V and the original cathepsin L, suggesting that both human genes have diverged since division from the common ancestor of rodent and primate lineages. It has been shown before that human cathepsin V is much less active than human cathepsin L on the usual cathepsin L synthetic substrates30. Similar to human cathepsin V, the murine cathepsin L is also much less active than human cathepsin L (Table 1). Although cathepsins L and V have high sequence identities (>70%) and structural similarities (Fig. 3), there are still subtle structural differences along the substrate-binding cleft31, which may give rise to the proteolysis activity difference and substrate specificity among these cathepsin enzymes. This warrants further investigation in the future.


Structural basis for the recognition and cleavage of histone H3 by cathepsin L.

Adams-Cioaba MA, Krupa JC, Xu C, Mort JS, Min J - Nat Commun (2011)

Sequence and structural conservation among human cathepsins L and V and murine cathepsin L.(a) Structure-based sequence alignment of cathepsins L and V. White residues on red background indicate identical residues, red residues on white represent similar residues and the other residues are coloured in black. (b) Surface representation of human cathepsins L, V and murine cathepsin L. The structure of murine cathepsin L is modelled based on human cathepsin L. The histone H3 peptide in human cathepsin L complex structure is superimposed to human cathepsin V and murine cathepsin L structures for comparison.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3105313&req=5

f3: Sequence and structural conservation among human cathepsins L and V and murine cathepsin L.(a) Structure-based sequence alignment of cathepsins L and V. White residues on red background indicate identical residues, red residues on white represent similar residues and the other residues are coloured in black. (b) Surface representation of human cathepsins L, V and murine cathepsin L. The structure of murine cathepsin L is modelled based on human cathepsin L. The histone H3 peptide in human cathepsin L complex structure is superimposed to human cathepsin V and murine cathepsin L structures for comparison.
Mentions: In the human genome, there are two similar proteases that had been called cathepsin L. The original cathepsin L was first isolated in the late 1970s28. In 1998, a second human protease was cloned29, which was first named as cathepsin L2 but is now referred to as cathepsin V. Human cathepsin V is very similar to cathepsin L in sequence (Fig. 3). The genes for human cathepsin V and cathepsin L are in close proximity on chromosome 9, hinting that they might come from recent gene duplication. In the case of the mouse, it seems that only one cathepsin L form exists, and it is intermediate between human cathepsin V and the original cathepsin L, suggesting that both human genes have diverged since division from the common ancestor of rodent and primate lineages. It has been shown before that human cathepsin V is much less active than human cathepsin L on the usual cathepsin L synthetic substrates30. Similar to human cathepsin V, the murine cathepsin L is also much less active than human cathepsin L (Table 1). Although cathepsins L and V have high sequence identities (>70%) and structural similarities (Fig. 3), there are still subtle structural differences along the substrate-binding cleft31, which may give rise to the proteolysis activity difference and substrate specificity among these cathepsin enzymes. This warrants further investigation in the future.

Bottom Line: Canonical substrate-cathepsin L interactions are observed in the complex between the protease and the histone H3 peptide.Systematic analysis of the impact of posttranslational modifications at histone H3 on substrate selectivity suggests cathepsin L to be highly accommodating of all modified peptides.This is the first report of cathepsin L-histone H3 interaction and the first structural description of cathepsin L in complex with a substrate.

View Article: PubMed Central - PubMed

Affiliation: Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, Ontario M5G 1L7, Canada.

ABSTRACT
Proteolysis of eukaryotic histone tails has emerged as an important factor in the modulation of cell-cycle progression and cellular differentiation. The recruitment of lysosomal cathepsin L to the nucleus where it mediates proteolysis of the mouse histone H3 tail has been described recently. Here, we report the three-dimensional crystal structures of a mature, inactive mutant of human cathepsin L alone and in complex with a peptide derived from histone H3. Canonical substrate-cathepsin L interactions are observed in the complex between the protease and the histone H3 peptide. Systematic analysis of the impact of posttranslational modifications at histone H3 on substrate selectivity suggests cathepsin L to be highly accommodating of all modified peptides. This is the first report of cathepsin L-histone H3 interaction and the first structural description of cathepsin L in complex with a substrate.

Show MeSH
Related in: MedlinePlus