PDBsum entry 7nip

Structural protein

PDB id

7nip

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Contents

			Protein chain

					40 a.a.

PDB id:

7nip

Links
- PDBe
- RCSB
- MMDB
- JenaLib
- Proteopedia
- CATH
- SCOP
- PDBSWS
- ProSAT

Name:

Structural protein

Title:

Titin n2a unique sequence (un2a) core

Structure:

Isoform 11 of titin. Chain: a. Synonym: connectin,rhabdomyosarcoma antigen mu-rms-40.14. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ttn. Expressed in: escherichia coli. Expression_system_taxid: 562

NMR struc:

10 models

Authors:

T.Zhou,M.Kovermann,J.R.Fleming,O.Mayans

Key ref:

T.Zhou et al. (2021). Molecular Characterisation of Titin N2A and Its Binding of CARP Reveals a Titin/Actin Cross-linking Mechanism. J Mol Biol, 433, 166901-166901. PubMed id: 33647290 DOI: 10.1016/j.jmb.2021.166901

Date:

13-Feb-21

Release date:

03-Mar-21

PROCHECK

	Headers

	References

Protein chain

Q8WZ42 (TITIN_HUMAN) - Titin from Homo sapiens

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Seq: Struc:					34350 a.a. 40 a.a.

Key:

PfamA domain

Secondary structure



		Enzyme reactions

Enzyme class:

E.C.2.7.11.1 - non-specific serine/threonine protein kinase.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

1.	L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
2.	L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

L-seryl-[protein]	+	ATP	=	O-phospho-L-seryl-[protein]	+	ADP	+	H(+)

L-threonyl-[protein]	+	ATP	=	O-phospho-L-threonyl-[protein]	+	ADP	+	H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1016/j.jmb.2021.166901	J Mol Biol 433:166901-166901 (2021)
PubMed id: 33647290

Molecular Characterisation of Titin N2A and Its Binding of CARP Reveals a Titin/Actin Cross-linking Mechanism.
T.Zhou, J.R.Fleming, S.Lange, A.L.Hessel, J.Bogomolovas, C.Stronczek, D.Grundei, M.Ghassemian, A.Biju, E.Börgeson, B.Bullard, W.A.Linke, J.Chen, M.Kovermann, O.Mayans.

ABSTRACT

Striated muscle responds to mechanical overload by rapidly up-regulating the expression of the cardiac ankyrin repeat protein, CARP, which then targets the sarcomere by binding to titin N2A in the I-band region. To date, the role of this interaction in the stress response of muscle remains poorly understood. Here, we characterise the molecular structure of the CARP-receptor site in titin (UN2A) and its binding of CARP. We find that titin UN2A contains a central three-helix bundle fold (ca 45 residues in length) that is joined to N- and C-terminal flanking immunoglobulin domains by long, flexible linkers with partial helical content. CARP binds titin by engaging an α-hairpin in the three-helix fold of UN2A, the C-terminal linker sequence, and the BC loop in Ig81, which jointly form a broad binding interface. Mutagenesis showed that the CARP/N2A association withstands sequence variations in titin N2A and we use this information to evaluate 85 human single nucleotide variants. In addition, actin co-sedimentation, co-transfection in C2C12 cells, proteomics on heart lysates, and the mechanical response of CARP-soaked myofibrils imply that CARP induces the cross-linking of titin and actin myofilaments, thereby increasing myofibril stiffness. We conclude that CARP acts as a regulator of force output in the sarcomere that preserves muscle mechanical performance upon overload stress.